genetica humana beta

8/2/2019 Genetica Humana Beta

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GENETICA HUMANA.-

Human genetic diseases and normal variations can be placed into one of

five categories:

1. single gene disorders (diseases or traits where the phenotypes are

largely determined by the action, or lack of action, of mutations atindividual loci);

2. multifactorial traits (diseases or variations where the phenotypes arestrongly influenced by the action of mutant alleles at several loci acting

in concert);

3. chromosomal abnormalities (diseases where the phenotypes are largely

determined by physical changes in chromosomal structure - deletion,inversion, translocation, insertion, rings, etc., in chromosome number -

trisomy or monosomy, or in chromosome origin - uniparental disomy);

4. mitochondrial inheritance (diseases where the phenotypes are affected

by mutations of mitochondrial DNA); and

5. diseases of unknown etiology that seem to "run in families."

About 1% of the approximately 4 million annual live births in the UnitedStates will have a single gene disorder that will be serious enough to require

special medical treatment or hospital care. Each of these single gene disorders,

often called Mendelian traits or diseases, is relatively uncommon. The

frequency often varies with ethnic background, with each ethnic group having

one or more Mendelian traits in high frequency when compared to the other

ethnic groups. For example, cystic fibrosis has a frequency of about 1/2000 births in Americans descended from western European Caucasians but is

much rarer in Americans of western African descent while sickle cell anemia

has a frequency of about 1/600 births in Americans of western African descent

but is much rarer in Caucasians. Greeks and Italians of Mediterranean descenthave a high frequency of thalassemia; Eastern European Jews have a high

frequency of Tay-Sachs disease; French Canadians from Quebec have a highfrequency of tyrosinemia, all when compared to other ethnic groups. It has

been estimated that each of us, each "normal" member of the human race iscarrying between 1 and 8 mutations which, if found in the homozygous state

would result in the expression of a Mendelian disease. Since we each have

between 50,000 and 100,000 genes (loci) it is unlikely that any two unrelated

individuals would be carrying the same mutations, even if they are from the

same ethnic background, thus most of our offspring are not suffering from a

genetic disease. Most Mendelian diseases are rare, affecting about 1/10,000 to


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1/100,000 live births as an order of magnitude estimate. In total they will add

to the 1% of live births mentioned above.

Mendelian traits, or single gene disorders, fall into 5 categories or modes

of inheritance based on where the gene for the trait is located and how many

copies of the mutant allele are required to express the phenotype:

1. autosomal recessive inheritance (the locus is on an autosomal

chromosome and both alleles must be mutant alleles to express the

phenotype)

2. autosomal dominant inheritance (the locus is on an autosomal

chromosome and only one mutant allele is required for expression of

the phenotype)

3. X-linked recessive inheritance (the locus is on the X chromosome and

both alleles must be mutant alleles to express the phenotype in females)

4. X-linked dominant inheritance (the locus is on the X chromosome and

only one mutant allele is required for expression of the phenotype in

females), and

5. mitochondrial inheritance (the locus is on the mitochondrial

"chromosome").

Mendel based his laws on mathematical probabilities that allowed

predictions of resulting phenotypes when certain crosses were made in thegarden pea. When he published in 1866, the discovery of the chromosomal

basis of inheritance (meiosis and gametogenesis) by Sutton, Boveri, andothers was still a generation away. Therefore, there was no physical basis for

explaining the Mendelian segregation ratios. The discoveries of Sutton,

Boveri, and others allowed a reexamination of Mendel's apparently forgotten

publication. In 1900, Correns, DeVries, and Tschermak, all independently

"rediscovered" Mendel's laws of segregation, and by 1902 the first human

Mendelian "inborn error of metabolism", alcaptonuria, was found by SirArchibald Garrod. Mendel's laws are grounded in the chromosomal

movements in meiosis, gametogenesis, and fertilization. Understanding the

fundamental processes of cell division is the key to understanding Mendelian

genetics.

MITOSIS and MEIOSIS

Mitosis is the process of cell division that is responsible for thedevelopment of the individual from the zygote (fertilized egg) to maturity


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(approximately 1014cells). It is the process by which the somatic cells divide

and maintain the same chromosomal complement. Each chromosomeduplicates forming two chromatids connected to a single centromere, the

centromeres line up on the metaphase plate without the homologous pairing

and recombination found in meiosis (except for sister chromatid exchange ofidentical DNA information in mitosis), and the centromere divides as each

chromatid now becomes a daughter chromosome at anaphase of cell division.

Mitosis is the process by which two identical daughter cells with identicalDNA complements are formed from one progenitor cell. Mutations can arise

during DNA replication in mitosis, just as they do in meiosis. These

mutations, and their consequences in somatic cell diseases, such as cancer, are

discussed in the molecular genetics lecture portion of this course. Most mitotic

divisions, and consequently the fastest rate of growth, occurs before birth in

the relatively protected environment of the uterus. Most of us only increase 15

to 30 times our birth weight (24

or 25

times) from birth to maturity, but fromconception to birth our weight increases many fold. Consequently, mostgenetic diseases are expressed at birth or during early development, although

some late onset human diseases, and somatic cell diseases, do occur.

Gelehrter, Collins, and Ginsburg, Chapter 2, should be read for a

complete description of the events and importance of mitosis

.

MEIOSIS and GAMETOGENESIS

Each somatic cell of a normal individual contains two copies of each of

the 22 autosomal chromosomes, one of paternal origin and one of maternalorigin, and either an X from the mother and an X from the father if the

individual is female or an X from the mother and a Y from the father if theindividual is male. This is called the diploid (2 copy) state. During

gametogenesis, the formation of the gametes (ova in females and sperm in

males), this diploid state is reduced to the haploid (1 copy) state through the

process of cell division called meiosis. Meiosis consists of two consecutivecytoplasmic divisions with only one DNA replication. In some texts meiosis

will be explained as two divisions, a reduction division followed by a mitoticdivision but this is a misnomer. Meiosis is one continuous process from

beginning to end.


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This diagram shows a

general summary of two pairsof chromosomes going

through meiosis. Only the

nucleus and the centrioles areshown. In A, the

chromosomal DNA is already

replicated and thehomologous chromosomes

are partially paired. In B,

pairing is completed but the

two chromatids of each

chromosome have not yet

condensed enough to be

visible. In C, both chromotidsof each chromosome arevisible and recombination

(chiasma), or crossing-over,

between chromatids of the homologous chromosomes are evident. In D, the

chiasmata (pl. of chiasma) are being resolved and the homologous

centromeres are lining up on the metaphase plate. E represents anaphase of the

first meiotic division. The centromeres of homologous chromosomes aremoving to the poles without dividing, thus separating the maternal centromere

from the paternal centromere along with their associated chromosomes thathave recombined. In F, the centromeres each of the haploid chromosomes

with its two chromatids are migrating to the metaphase plate. G shows the

centromeres dividing and moving toward the poles in early anaphase of the

second meiotic division. H demonstrates the nuclei of the 4 haploid products

that result from the meiotic division of one initial diploid cell.

In humans, none of the four haploid products is identical, sincerecombination occurs at least once for each chromatid, but they all contain the

same amount of DNA and each contains 23 chromosomes. The chromosomal

movements in oogenesis and spermatogenesis in humans will be covered morecompletely in the section on chromosomal abnormalities. It is presented here

to show the chromosomal movements required to fulfill Mendel's laws.

Gelehrter, Collins, and Ginsburg, Chapter 2 should be read for a more

complete introduction to meiosis and the structure of human

chromosomes.

Mendel assumed that the traits he was studying were determined by what

he called unit characters. We call these unit characters alleles. Alleles are the

alternative forms of a gene, often called the locus or specific site on thechromosome where the gene resides. Mendel's law of segregation states that


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during gametogenesis

these alternative forms,alleles, segregate into

different gametes and

are never found in thesame gamete. The

chromosomal

movements in meiosis assure this.

The above sketch reviews the chromosomal movements of first meiotic

division. [A], represents two homologous chromosomes in a cell that is goingto enter meiosis, one chromosome was inherited from the mother and one

inherited from the father. Each chromosome contains a single double stranded

DNA molecule. Each has a different allele at a particular locus. [B], the

chromosomes have duplicated, forming two chromatids (two double-strandedDNA molecules) and paired at the metaphase plate in the first division of

meiosis. [C], the homologous chromosomes have separated at the firstdivision. Notice that the alleles are destined to go into separate gametes. The

effects of recombination are not shown.

Mendel's law of independent assortment states that unit characters for

different traits, traits controlled by genes of different chromosomes assort

independently. That is, if a gene on chromosome 1 has two alleles, a and b,

and a gene on chromosome 2 has two alleles, c and d, the

combinations a and c, a and d, b and c, and b and d, are all equally likely.There is no preference for a to be with either c or d. Since chromosmes 1 and2 line up on the metaphase plate independently at the first meiotic division,

with equal chance of the maternal or paternal homolog going to one pole foreach chromosome, these combinations have an equal chance of occurring.

Thus, alleles of genes that lie on different chromosomes assort independently

of one another. These two laws, the law of segregation and the law of

independent assortment, are the basis of Mendelian inheritance.

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or the

CurrentLesson

link (also

the fourthicon from

the top of

the

navigation bar).

he study of inherited Mendelian traits in humans must rely onobservations made while working with individual families. Classical cross

fertilization breeding experiments as performed by Mendel are not allowed in

humans! Human geneticists are not allowed to selectively breed for the traits

they wish to study! One of most powerful tools in human genetic studies is

pedigree analysis. When human geneticists first began to publish familystudies, they used a variety of symbols and conventions. Now there are agreedupon standards for the construction of pedigrees.

Males are always represented by square symbols, females with circular

symbols. A line drawn between a square and a circle represents a mating of

that male and female. Two lines drawn between a square and a circle indicate

a consanguineous mating, the two individuals are related, usually secondcousins or closer relatives. When possible, the square should be placed on theleft and the circle on the right of the mating line. Generations are connected

by a vertical line extending down from the mating line to the next generation.Children of a mating are connected to a horizontal line, called the sibship line,

by short vertical lines. The children of a sibship are always listed in order of

birth, the oldest being on the left. Sometimes to simplify a pedigree only one

parent is shown, the other is omitted. This neither signifies parthenogenic

development nor does it signify divinely inspired conception, it merely means

the parent left out is not from the family being studied and is genotypicallyhomozygous normal for the trait being studied. Normal individuals are


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represented by an open square or circle, depending upon the gender, and

affected individuals by a solid square or circle. Each generation is numberedto the left of the sibship line with Roman Numerals. Individuals in each

generation are numbered sequentially, beginning on the left, with Arabic

Numerals. For example the third individual in the second generation would beidentified as individual II-3.

For more information on the construction and interpretation of pedigrees

consult Gelehrter, Collins, and Ginsburg, 2nd edition, Chapter 3.

AUTOSOMAL DOMINANT INHERITANCE

The pattern of autosomal dominant inheritance is perhaps the easiest typeof Mendelian inheritance to recognize in a pedigree. One dose of the mutant

gene, one mutant allele, is all that is required for the expression of the

phenotype. There are three reasons why an individual with an autosomal

dominant disease should always be considered as being a heterozygote until

proven otherwise:

1. The disease is usually rare, with only about 1/10,000 individualsaffected as an order of magnitude. To produce a homozygote, two

affected heterozygotes would have to mate. This probability is

1/1,000,000 and then they would have only a 1/4 chance of having ahomozygous affected offspring. Affected individuals are most likely to

come from affected by normal matings. The normal parent is

homozygous recessive, thus assuring that each product of the mating

has at least one normal gene.

2. In the extremely rare instances where two affected individuals have

mated, the homozygous affected individuals usually are so severely

affected they are not compatible with life. The exceptions are theautosomal dominant diseases caused by the somatic expansion of

trinucleotide repeat sequences (e.g., Huntington's disease) that we willstudy later.

3. The mating of very closely related individuals, the most likely way fortwo affected individuals to know each other, is forbidden in our society.

With the understanding that almost all affected individuals areheterozygotes, and that in most matings involving a person with an autosomal

dominant trait the other partner will be homozygous normal, there are four

hallmarks of autosomal dominant inheritance.


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1. Except for new mutations, which are rare in nature and extremely rare

on examination pedigrees, and the complexities of incompletepenetrance to be discussed later, every affected individual has an

affected biological parent. There is no skipping of generations.

2. Males and females have

an equally likely chance

of inheriting the mutant

allele and being affected.

The recurrence risk of

each child of an affected

parent is 1/2.

3. Normal siblings of

affected individuals do not transmit the trait to their offspring.

4. The defective product of the gene is usually a structural protein,

not an enzyme. Structural proteins are usually defective when one of

the allelic products is nonfunctional; enzymes usually require bothallelic products to be nonfunctional to produce a mutant phenotype.

THE PUNNET SQUARE

In 1910, Punnett developed a simple method of depicting the possible

genotypes one could get from various matings. We call it the Punnett Square.

Its use in predicting the genotypic ratios in the offspring is illustrated below:

Suppose a father is heterozygous for an autosomal dominant gene, with

allele D, the mutant dominant allele, and allele d, the recessive normal allele.

He can produce two types of gametes, D and d. Suppose also his wife ishomozygous normal, having both d alleles. The Punnett Square is constructed

as follows:

One gamete comes from each parent to produce the genotype of the

offspring. Two out of the four possible combinations are affected; two out

of four are normal.



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Sample

P

e

di

gr

e

e

The family represented by Pedigree 1 is a good example of how

autosomal dominant diseases appear in a pedigree. Each of the four hallmarks

of autosomal dominant inheritance are fulfilled. Each affected individual hasan affected parent; there is no skipping of generations. Males and females areequally likely to be affected. About 1/2 of the offspring of an affected

individual are affected (the recurrence risk is 1/2). Normal siblings (II-3) of

affected individuals have all normal offspring. Low density lipoprotein

receptors are structural proteins or polypeptides, not enzymes. If III-1, anaffected female, were to produce a child that child would have a 1/2 chance of

being normal and a 1/2 chance of being affected. If her normal brother, III-2,were to produce a child that child would have a nearly 0 chance of being

affected.

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MENDELIAN INHERITANCE

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ince every mutant allele for an autosomal dominant disease is

expressed, and by definition a disease is a deleterious phenotype, howdo autosomal dominant diseases stay in the population? Shouldn't they

be eliminated by natural selection against deleterious phenotypes? There

appears to be four phenomena that maintain these deleterious alleles in thepopulation:

1. Variable Expressivity

2. Late Onset

3. High Recurrent Mutation Rate

4. Incomplete Penetrance

VARIABLE EXPRESSIVITY

One example of variable expressivity is Marfan syndrome. Marfan

syndrome is an autosomal dominant disease caused by a mutation in collagen

formation. It affects about 1/60,000 live births. Symptoms of Marfan

syndrome include skeletal, optical, and cardiovascular abnormalities. Skeletal

abnormalities include arachnodactyly (long fingers and toes), extremelengthening of the long bones, scoliosis, rib and sternum abnormalities,

among others. Optical abnormalities almost always include ectopia lentis, adislocation of the lens into the anterior chamber of the eye. Cardiovascular

abnormalities may be numerous and include possible dissecting aneurysms,which are largely responsible for the shorter life span of Marfan syndrome

patients as a group. Each patient may express all of the symptoms, or only a

few. That is variable expressivity. Each patient with the mutant allele for

Marfan syndrome expresses at least one of the symptoms, but the physicianmay have to look closely. Almost all are taller than average, but a lot of non-

Marfan individuals are tall. Almost all have long fingers, but so do a lot ofnon-Marfan persons. Some may be very mildly affected and lead normal lives

while others, more severely affected, have a shorter life expectancy. The

disease is maintained in the population through recurrent mutations and the

matings of less severely affected individuals with normal individuals. Theextent of severity of affected does not affect the severity of expression in the

next generation, that is, the offspring of mildly affected individuals rangefrom mildly affected to severely affected, with equal probability.

For a more complete description and other examples of variable

expressivity see Gelehrter, Collins, and Ginsburg, 2nd ed., Pages 29

and 30.

LATE ONSET


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Some autosomal dominant diseases do not express themselves until later

in life, well beyond the reproductive years. The individuals who will developthe disease have passed the mutant allele along to their offspring before they

themselves know they are affected. In some cases even grandchildren are born

before the affected grandparent shows the first signs of the disease.Huntington disease, sometimes called Huntington's Chorea because of the

choreic movements expressed as the disease progresses, is a good example of

a late onset disease. Age of onset varies from the teens to the late sixties, witha mean age of onset between ages 35 and 45. Nearly 100% of the individuals

born with the defective allele will develop the disease by the time they are 70.

The disease is progressive with death usually occurring between four and

twenty-five years after the first symptoms develop. Emotional changes often

are the first symptoms.

At the gene level, it is caused by the expansion of an unstabletrinucleotide repeat sequence, CAG, in the coding region of the gene. What is

inherited at birth in Huntington disease is a gene with several repeats and theinstability that allows somatic recombination and extension. Somatic

mutations introduced by the expansion of trinucleotide repeat sequences donot have to occur in coding regions to produce a mutant allele. Other diseases,

such as myotonic dystrophy, an autosomal dominant disease where expression

is delayed, result from molecular defects at the gene level that are caused by

the expansion of unstable trinucleotide sequences. (In the case of myotonicdystrophy the sequence is CTG.) However, this unstable sequence lies in a

non-translated region of the gene. In both diseases the size of the inheritedexpansion correlates to the age of onset or the severity of disease, but is not

absolutely predictable on an individual basis. One cannot sequence the gene

and precisely predict the age of onset of Huntington disease.

HIGH RECURRENT MUTATION RATE

Achondroplasia is one of the major causes of dwarfism. Motor skills may

not develop as quickly as their normal siblings, but intelligence is not reduced.It occurs in about 1/10,000 live births.

Like many autosomal dominant diseases, individuals homozygous for themutant allele do not survive to term. Almost 85% of the cases are the result of

new mutations, where both parents have a normal phenotype. The mutationrate for achondroplasia may be as much as 10 times the "normal" mutation

rate in humans. This high recurrent mutation is largely responsible for keeping

the mutant gene in the population at its present rate. Several other autosomal

dominant genetic diseases have high recurrent mutation rates butachondroplasia is probably the best known.


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INCOMPLETE PENETRANCE

Incomplete penetrance should never be confused with variable

expressivity. In diseases with variable expressivity the patient alwaysexpresses some of the symptoms of the disease and varies from very mildly

affected to very severely affected. In autosomal dominant diseases with

incomplete penetrance, the person either expresses the disease phenotype orhe/she doesn't. Incomplete penetrance and variable expressivity are

phenomena associated only with dominant inheritance, never with recessiveinheritance. The following pedigree illustrates incomplete penetrance in a

known autosomal dominant disease.

In the above pedigree, there is ample evidence for autosomal dominantinheritance:

The disease is passed from the father (II-3) to the son (III-5), this never

happens with X-linked traits.

The disease occurs in three consecutive generations, this never happens

with recessive traits.

Males and females are affected, with roughly the same probability.


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However, II-1 does not express the disease. He must have inherited the

mutant allele because he passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he has the allele for

the disease but he does not express it.

Late onset, high recurrent mutation rate, variable expressivity, and

incomplete penetrance only occur in autosomal dominant diseases, never in

recessive diseases unless there is medical intervention to prevent thedevelopment of symptoms in neonatal children.

AUTOSOMAL RECESSIVE INHERITANCE

he first, and most important, thing to remember about

autosomal recessive inheritance is that most, if not all, affected

individuals have parents with normal phenotypes.

Why? Suppose the disease affects one in ten thousand live births, a good

order of magnitude estimate for most autosomal recessive diseases. That

would make the heterozygote frequency in the population one in fifty (see

population genetics for calculations). The likelihood of two affected personsmating would be 1/10,000 x 1/10,000 or 1/100,000,000. By chance alone

there might be two such matings in the Unites States, but no more than 2. The

likelihood of an affected and a heterozygote mating would be 1/10,000 x 1/50x 2(since either parent could be the affected) or 1/250,000. The likelihood of

two heterozygotes (heterozygotes are usually called "carriers") mating is 1/50

x 1/50 or 1/2500, more than 99% of all possible matings. The Punnett Square

for autosomal recessive diseases with an affected child in the family almost

always looks like the following:

Where the father andmother are both Dd (dd is therecessive affected

individual, Dd the heterozygous

carrier individual, and DD the

homozygous normal individual). The Punnet Square shows the origin of the

famous Mendelian ration of 3/4 normal to 1/4 affected. For most autosomal

recessive diseases, but not all, the heterozygote cannot be distinguished fromthe normal homozygote. In the normal phenotype categories of offspring in

the above Punnett Square (Dd and DDproduce the same normal phenotype),


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please note that two of the three are heterozygotes (carriers); one of the three

is homozygous normal.

Within the normal siblings of an affected individual the probability of

being a carrier is 2/3.

There are five hallmarks of autosomal recessive inheritance:

1. Males and females are equally likely to be affected.

2. On average, the recurrence risk to the unborn sibling of an affected

individual is 1/4.

3. The trait is characteristically found in siblings, not parents of

affected or the offspring of affected.

4. Parents of affected children may be related. The rarer the trait in

the general population, the more likely a consanguineous mating is

involved.

5. 5. The trait may appear as an isolated (sporadic) event in small

sibships.

The above pedigree illustrates four of the five hallmarks of autosomal

recessive inheritance. I-1 and I-2 are unrelated, yet they produced an affectedoffspring (affected offspring have normal parents). By chance, they both

must have been carriers. Even though II-2 is affected, she produced no

affected offspring (trait appears in siblings, not parents or offspring). Byfar the most probable genotype for an individual from outside the family (II-1)


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is homozygous normal. III-1, III-2 and III-3 are all obligate carriers

(heterozygotes), since they are not affected but could only have inherited therecessive gene from II-2 II-3, II-5, and II-6 each have a 2/3 chance of being a

carrier and a 1/3 chance of being homozygous normal. They are not affected,

but they come from a carrier x carrier mating. II-4 and II-7 have a highprobability of being homozygous normal since they are from outside the

family. III-4, III-5, III-6, III-7, III-8, and III-9 all have a 1/3 chance of being

carriers and a 2/3 chance of being homozygous normal. One parent of each isprobably homozygous normal, the other has a 2/3 chance of being a carrier

and a 1 in 2 chance of passing on the recessive allele if they were a carrier.

When consanguinity is involved, i.e., matings between related

individuals, in the production of an affected child the assignment of

probabilities changes, especially in the rarer autosomal recessive diseases.

Since these relatively rare autosomal recessive diseases would have diseasefrequencies of 1/10,000 live births or less, the carrier frequency in the general

population would not exceed 1/50. Normal individuals from the generalpopulation would have a probability of at least 49 to 1 of being homozygous.

Consanguinity introduces the possibility of one founding parent being acarrier, with the recessive allele being passed through carrier offspring and

meeting itself to produce an affected homozygous offspring some generations

later. When an affected child is produced as the result of a consanguineous

mating, those individuals in the direct line of descent are most probablycarriers and those from outside the family are most probably normal

homozygotes. In the following pedigree, V-1 is affected with an autosomalrecessive disease. Her parents are second cousins, a legal marriage in most

states. IV-1 and IV-2 must both be carriers since they produced an affected

child. (The child must have received a recessive allele from each of her

parents.) III-2 is an obligate carrier. Her father was affected, and hence, a

homozygote for the recessive allele. III-5 must also be heterozygotes since IV-

2 had to get her recessive allele from one of her parent, and the chance of III-6being a carrier is less than 1 in 50. I-1 and I-2 must both have been carriers

since they produced an affected offspring, II-1.


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Normally

one never

considers the

possibility of

two unrelated

individuals both being

carriers unlessthere is

evidence to the

contrary. Here

I-1 and I-2 arethe exception

to the rule.There is evidence that both must be carriers.

Before he had any children, II-5 had a 2/3 chance of being a carrier and a1/3 chance of being homozygous normal (The normal siblings of affected rule

explained above). But III-5 had to get her recessive allele from someone, and

her other parent, II-6 had at most a 1/50 chance before her children were born.

One can compare the two probabilities and calculate that in at least 100 out of

103 times II-5 will be the carrier. This is so close to 1 that for practicalpurposes one can say he is the carrier. In rare autosomal recessive diseases,when consanguinity is involved, those individuals in the direct line of

descent within the family are considered to be carriers and those

individuals from outside the family are considered homozygous normal

unless there is evidence to the contrary.

What can we say about the carrier probabilities of the individuals within

the family that are not in the direct line of descent to the affected child? In the

above pedigree, III-1 must be a carrier. She is not affected, but she must havereceived a recessive allele from her father (II-1) who is homozygousrecessive. II-3 and II-4 each have a 2/3 chance of being a carrier since they are

phenotypically normal and come from a heterozygote x heterozygote mating.III-6 has a one in two chance of being a carrier. His father is a carrier (see

above calculations) and his mother is from outside the family.

In human genetics counseling it doesn't help your patient to understand

and make decisions when you are quoting statistics to the second or third

decimal point. 49/100 or 0.488 are close to one half. One out of two, or one

half, is a number your patient is more likely to understand and remember. Youmay get into trouble for using certainty (zero or 100%), or even ridiculous


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numbers like 1/1,000,000, when something doesn't go as you predicted, but

not for rounding off to the nearest fraction. Always make your counselingcalculations as accurately as possible, but make sure they are presented in a

form that is something your patient will comprehend.


X-LINKED INHERITANCE

hen the locus for a gene for a particular trait or disease lies on theX chromosome, the disease is said to be X-linked. The inheritance

pattern for X-linked inheritance differs from autosomal inheritance only

because the X chromosome has no homologous chromosome in the male, themale has an X and a Y chromosome. Very few genes have been discovered on

the Y chromosome.

The inheritance pattern follows the pattern of segregation of the X and Y

chromosomes in meiosis and fertilization. A male child always gets his X

from one of his mother's two X's and his Y chromosome from his father. X-linked genes are never passed from father to son. A female child always

gets the father's X chromosome and one of the two X's of the mother. An

affected female must have an affected father. Males are always hemizygousfor X linked traits, that is, they can never be heterozygoses or

homozygotes. They are never carriers. A single dose of a mutant allele will

produce a mutant phenotype in the male, whether the mutation is

dominant or recessive. On the other hand, females must be either

homozygous for the normal allele, heterozygous, or homozygous for themutant allele, just as they are for autosomal loci.

X-LINKED DOMINANT INHERITANCE

When an X-linked gene is said to express dominant inheritance, it means

that a single dose of the mutant allele will affect the phenotype of the female.

A recessive X-linked gene requires two doses of the mutant allele to affect the

female phenotype. The following are the hallmarks of X-linked dominant

inheritance:

The trait is never passed from father to son.

All daughters of an affected male and a normal female are affected.All sons of an affected male and a normal female are normal.


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Matings of affected females and normal males produce 1/2 the sons

affected and 1/2 the daughters affected.

Males are usually more severely affected than females. The trait

may be lethal in males.

In the general population, females are more likely to be affected

than males, even if the disease is not lethal in males.

The following Punnett Squares explain the first three hallmarks of X-

linked dominant inheritance. X represents the X chromosome with the normalallele, XA represents the X chromosome with the mutant dominant allele, and

Y represents the Y chromosome. Note that the affected father never passes the

trait to his sons but passes it to all of his daughters, since the heterozygote is

affected for dominant traits. On the other hand, an affected female passes thedisease to half of her daughters and half of her sons.

Father's

Gametes Father's Gametes

XA Y X Y

Mother's

Gametes

X XXA XY Mother's

Gametes

XA XAX XAY

X XXA XY X XX XY

Figure 1. Affected father x normal mother. Figure 2. Affected mother x normal father.

Males are usually more severely affected than females because in eachaffected female there is one normal allele producing a normal gene product

and one mutant allele producing the non-functioning product, while in each

affected male there is only the mutant allele with its non-functioning product

and the Y chromosome, no normal gene product at all. Affected females aremore prevalent in the general population because the female has two X

chromosomes, either of which could carry the mutant allele, while the maleonly has one X chromosome as a target for the mutant allele. When the

disease is no more deleterious in males than it is in females, females are about

twice as likely to be affected as males. As shown in Pedigree 5 below, X-

linked dominant inheritance has a unique heritability pattern.


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The key for determining if a dominant trait is X-linked or autosomal is to

look at the offspring of the mating of an affected male and a normal female. If

the affected male has an affected son, then the disease is not X-linked. All of

his daughters must also be affected if the disease is X-linked. In Pedigree 5,

both of these conditions are met.

What happens when males are so severely affected that they can'treproduce? Suppose they are so severely affected they never survive to term,

then what happens? This is not uncommon in X-linked dominant diseases.

There are no affected males to test for X-linked dominant inheritance to see if

the produce all affected daughters and no affected sons. Pedigree 6 shows theeffects of such a disease in a family. There are no affected males, only

affected females, in the population. Living females outnumber living malestwo to one when the mother is affected. The ratio in the offspring of affected

females is: 1 affected female: 1 normal female: 1 normal male.


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Pedigree 6.

You will note that in Pedigree 6 there have also been several spontaneous

abortions in the offspring of affected females. Normally, in the general

population of us normal couples, one in six recognized pregnancies results ina spontaneous abortion. Here the ratio is much higher. Presumably many of

the spontaneous abortions shown in Pedigree 6 are males that would have

been affected had they survived to term.

X-LINKED RECESSIVE INHERITANCE

veryone has heard of some X-linked recessive disease even though

they are, in general, rare. Hemophilia, Duchenne muscular dystrophy,

Becker muscular dystrophy, and Lesch-Nyhan syndrome are relativelyrare in most populations, but because of advances in molecular genetics theyreceive attention in the media. More common traits, such as glucose-6-

phosphate dehydrogenase deficience or color blindness, may occur frequently

enough in some populations to produce a few affected females. However,

their effect on individuals is rarely life threatening and medical intervention is

not needed. Pedigree 7 shows one typical inheritance pattern for a rare X-

linked recessive disease.

In Pedigree 7

above, which of the

following females

is least likely to be

a heterozygote for

the rare X-linkedrecessive gene, III-

1, III-3, or III-5?The answer of

course is III-3. III-1

and III-5 each have

a 1/2 chance of

being a carrier but

III-3 has almost a 0 chance of being a carrier. Why? Let's look atthe PunnettSquares for X-linked recessive inheritance.

Affected Father's

Genotype

Normal Father's

Genotype

XA Y X Y


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Normal

Mother's

Genotype

X XXA XY Carrier

Mother's

Genotype

XA XAY XAY

X XXA XY X XX XY

All daughters carriers, all sons normal.Half of sons affected, half of daughters

carriers.

In Pedigree 7, II-2 and II-5 are both carriers, their father was affected and

passed on his only X chromosome to his daughters. II-3 cannot be a carrier for

two reasons. First, males are either affected or normal, never carriers. Second,

he didn't inherit his father's X chromosome. He inherited his father's Ychromosome. III-3 couldn't have been a carrier since neither her father nor her

mother had the mutant gene.

What are the hallmarks of X-linked recessive inheritance?

As with any X-linked trait, the disease is never passed from father

to son.

Males are much more likely to be affected than females. If affected

males cannot reproduce, only males will be affected.

All affected males in a family are related through their mothers.

Trait or disease is typically passed from an affected grandfather,

through his carrier daughters, to half of his grandsons.

Counseling in X-linked recessive diseases is a bit more complex than it is

in autosomal recessive diseases. In X-linked recessive diseases, Bayes

theorem, or Bayesian probability must be used to accurately calculate carrier

probabilities. In some pedigrees these probabilities change as new information

appears. Sometimes we use Bayesian probability without recognizing it.

Consider the following:

A patient of yours is getting married and comes to you for counseling. She has

a brother with a rare X-linked recessive disease. Her mother's father also hadthe disease. She wants to know the probability of her being a carrier of the

disease and the probability that she will pass the disease to her children.

What is your advice?

Being a reasonably good human geneticist, you tell her that her motherwas a carrier and that she has a one chance in two of being a carrier,

depending upon which of her mother's X chromosomes she inherited. You

also explain that if she is a carrier she will pass the affected X to her son one


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half of the time, but that her daughters will not be affected because they will

always get a normal X from their father. Excellent advice!

But now suppose the conditions change. Her first child is a boy and he is

affected. Now what is the probability that she is a carrier? Of course this

probability changes from 1/2 to 1. That is the basis for Bayesian probability.

The individual undergoing counseling has an a prioricalculated probability of

being a carrier (not certainty) and later developments alter this probability.

Now suppose this patient who came to you for counseling had a normalson, not an affected son. Shouldn't her probability of being a carrier be

changed? Yes it should, but it is more complex than moving from 1/2 to 1 as itdid with the affected son. The following is an example of how probabilities

change with normal sons.

Probability of

CarrierNon-

Carrier

At Birth 1/2 1/2

At birth she had an equal chance of being a carrier or a non-carrier, her

mother was a known carrier.

What is the probability of 1 normal son, given that she is a carrier?

Answer: 1/2

What is the probability of 1 normal son, given that she is a non-carrier?

Answer: 1

Probability of

CarrierNon-

Carrier

At Birth 1/2 1/2

One Normal Son 1/2 1

The joint probability of both events happening is the product of each

separate event. The probability of being a carrier and also having one normal

son is 1/2 x 1/2. The probability of being a non-carrier and having a normal

son is 1/2 x 1.

Probability of

CarrierNon-

Carrier

At Birth 1/2 1/2

One Normal Son 1/2 1Joint Probability 1/4 1/2


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Since your patient is either a carrier or a non-carrier, we need to calculate

the relative probability of each possibility. To do this we must make the jointprobabilities add to 1. This is done by dividing each joint probability by the

sum of the joint probabilities.

Probability of

Carrier Non-Carrier

At Birth 1/2 1/2

One Normal Son 1/2 1

Joint Probability 1/4 1/2

Relative Probability (1/4)/(1/4+1/2)=1/3 (1/2)/(1/4+1/2)=2/3

The relative probability of your patient being a carrier after the birth of

one normal son is 1/3 and the relative probability of her not being a carrier is

now 2/3. Just as the probability changed after the birth of an affected son, italso changes after the birth of a normal son.

Now, if she has another son and he is normal, her probability of being a

carrier and producing two normal sons would be 1/2 x 1/2 x 1/2. The jointprobability is now 1/8 of being a carrier. The joint probability of not being a

carrier would be 1/2 x 1 x 1. It would remain at 1/2. The relative probability of

being a carrier would drop to 1/5. The relative probability of not being a

carrier would increase to 4/5.

However, if she were to have a third son and he were affected, all of thisBayesian probability calculation would not be necessary. She would be aknown carrier. If she were a non-carrier, her affected son would have to be a

new mutation. This is not an impossibility for X linked recessive diseasesbecause it only requires one mutational event to be expressed in males, but

when it is factored in the Bayesian probability tables above as a probability of

10-5, it shifts the probability of being a carrier to almost certainty.


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Pedigree 8 shows a family with a rare X-linked recessive trait. For which

of the following females should Bayesian probability be used to calculate the

carrier probability, II-2, II-5, III-2, III-5, or III-7? II-2 and II-5 are both certain

carriers, their father was affected and they produced affected sons. III-2 andIII-5 each had a 1/2 chance of being carriers at birth. One of them has one

normal son, the other has had two normal sons. These are Bayesianprobabilities. III-7 is related to the affected individuals of the family through

her father. She has an almost 0 chance of being a carrier.


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Pedigree 9 demonstrates the one other common use of Bayesian

probability in counseling. Two requirements must be met. The disease mustbe a genetic lethal, that is, individuals with the disease cannot reproduce. An

example of such a disease is Duchenne muscular dystrophy. The proband

must be the only affected individual in the family. When these two conditionsare met, as they are in Pedigree 9, there is a reasonable possibility that the

affected individual, III-1, is a new mutation.

What is the probability that any female in the population where there isno history of the disease is a carrier of the Duchenne muscular dystrophy

gene? She could be a new mutation. If the mutation rate is u, her probabilityof being a new mutation would be 2u because she has two X chromosomes

and each could be mutated. Her mother could have been a new mutation (2u)

with a 1/2 chance of passing it to her daughter. Her grandmother could have

been the new mutation (2u), with a 1/4 chance of passing the mutant allele toher granddaughter. (Note that the father has no part in the equation since he is

normal - affected males cannot reproduce.) Her great-grandmother could havebeen the new mutation (2u) with a 1/8 chance of passing the mutation to her

great-granddaughter, etc. Since these are all independent ways to produce acarrier female, the probabilities sum:

2u + 1/2(2u) + 1/4(2u) + 1/8(2u) + 1/16(2u) + ... = 4u

A female with no history of the disease in her family has a 4u chance of

being a carrier before her first son is born. She has a 1-4u chance of not beinga carrier. This is close enough to 1 for the purposes of our Bayesian

calculations. The Bayesian table for II-2 in Pedigree 9 looks like this:

Probability of

Carrier Non-Carrier

At Birth 4u 1-4u=1

Probability of one affected child 1/2u

(III-1 was a new mutation)

(III-1)

Joint Probability 2u u

Relative Probability 2/3 1/3

Even though II-3 has produced an affected son, under the above two

conditions she still has only a 2/3 chance of being a carrier. 1/3 of all

Duchenne muscular dystrophy children born into families with no history of

the disease must be new mutations. This is true only of X-linked recessive

diseases where the affected males cannot reproduce.


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SEX LIMITED INHERITANCE

n some X-linked recessive diseases, such as Duchenne musculardystrophy, expression of the disease phenotype is limited exclusively to

males. In some X-linked dominant traits, such as incontinentia pigmenti

or orofaciodigital syndrome (OFD 1), expression is limited to females, males

do not survive to term. However, the expression of a disease in only one

gender does not necessarily imply that the disease is X-linked. There are

autosomal diseases that are limited to expression in only one sex. Precocious puberty and beard

growth are factors

expressed only inmales. The

hereditary form of

prolapsed uterus isexpressed only in

females. These arecalled sex limited

traits.

MITOCHONDRIAL INHERITANCE

The DNA of mitochondria contains about ten genes involved in oxidative

phosphorylation, as well as a few other genes. This DNA is capable of

mutation, so it is not surprising that a few human diseases have been found to

be associated with mitochondrial inheritance. Leber optic atrophy is a classicexample of a disease of mitochondrial DNA. The ovum, originating in the

female, has about 100,000 copies of mitochondrial DNA; the sperm,originating in the male, has fewer than 100 copies, and these are probably lost

at fertilization. Virtually all of ones mitochondria come from his, or her,

mother. Affected fathers produce no affected offspring, while the offspring ofaffected mothers are all affected. Figure 3 below shows the typical

mitochondrial inheritance pattern.

Figure 3 Mitochondrial inheritance pattern.

IMPRINTING


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Prader-Willi syndrome affects between 1/10,000 and 1/30,000 live births.

The study of this disease led to the discovery that, for some genes, the originof the gene may be important. For some loci the gene inherited from the father

acts differently from the gene inherited from the mother, even though they

may have the same DNA. This phenomenon is called imprinting. About 75%of patients with Prader-Willi syndrome have a small deletion of the long arm

of chromosome 15, a small piece of one chromosome 15 is missing while the

homologous chromosome remains intact. When this deletion is on the paternalchromosome (the father's genes are missing) Prader-Willi syndrome results.

When this deletion is on the maternal chromosome (the mother's genes are

missing) Angelman syndrome results. The two diseases have very different

clinical symptoms. The other 25% of Prader-Willi syndrome patients are

almost all the result of uniparental disomy, a rare chromosomal event in which

both chromosomes come from a single parent. (This will be covered later

under chromosomal diseases.) When both chromosomes 15 are derived fromthe mother, Prader-Willi syndrome results. When both chromosomes 15 arederived from the father, Angelman syndrome results. For normal development

an individual must inherit one copy of this chromosomal region from his or

her father and one from his or her mother. Several other regions have been

found to show uniparental disomy without this effect on the phenotype. Small

deletions usually affect the phenotype but they produce the same phenotype

whether of maternal or paternal origin. Through some unknown mechanism,the gene, or genes, involved in Prader-Willi and Angelman syndrome know

their origin and behave according to that origin. At the present time we do notknow whether this is a general phenomenon or not. It might be limited to this

small region of chromosome 15. It might be quite wide spread. Imprinting

represents an exception to Mendel's laws and remains an important area of

research.

CHROMOSOMAL INHERITANCE

IMPORTANCE

here are about five million conceptions in the United States eachyear, give or take a few hundred thousand. Consider the fate of 10,000

randomly chosen from these five million.

About 800 are chromosomally abnormal.

Of these 800:

At least 140 are 45, X. They lack an X or a Y chromosome.

At least 110 have an extra chromosome 16. At least 20 have an extra chromosome 18.


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At least 40 have an extra chromosome 21.

The rest have various different chromosomal abnormalities.

Of the 800 chromosomally abnormal conceptions, about 750 will abort

spontaneously:

139 of the 140 who lack an X or a Y chromosome will abort

spontaneously.

All of those with an extra chromosome 16 will abort spontaneously.

19 of the 20 with an extra chromosome 18 will abort spontaneously.The survivor will have a very short life expectancy.

35 of the more than 40 with an extra chromosome 21 will abortspontaneously. The survivors will have Down syndrome.

There are a variety of conceptions with other chromosomes extra. All

will be aborted spontaneously.

The remaining 50 individuals with chromosomal abnormalities will make

it to birth. Among them should be about:

1 with an extra chromosome 18 1 with a missing X or Y chromosome

10 with an extra chromosome 21 15 with an extra X or Y chromosome, and

about 20 with abnormal chromosomal rearrangements of various sorts,

at least 4 of which will result in Down syndrome.

Chromosomal abnormalities are an important component of medical

practice. You will see examples of them in your work and your everyday life.

KARYOTYPE

Specific chromosomal abnormalities were very difficult to identify prior

to 1956. In that year, Tjio and Levan published their method for visualizing

the chromosomes and revolutionized cytogenetics. They made it possible toaccurately count the chromosomes and determine in which of 7 groups of

chromosomes the error occurred (Groups A through G). Their methods startednearly two decades where research on chromosomal abnormalities was the

focus of human genetics. Shortly after their discovery, this intense study led to

other advances in techniques that allowed for the identification of individual

chromosomes by differential staining, resulting in unique banding patterns for

each chromosome. Now even very small regions can be visualized. To

identify chromosomes, they are arrested in late prophase or early metaphase ofmitosis, when the chromosomes are duplicated and condensed, but the

centromere has not yet divided. Each chromosome consists of two chromatidsat this stage. They are stained, photographed and arranged in a particular


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order,

from

largest to smallest, in what is called a karyotype. An example of the karyotype

of a normal male is shown in Figure 4 below. The chromosomes are grouped

by size and location of the centromere (metacentric, submetacentric, and

acrocentric).

Figure 4. Karyotype.

There is also a standard nomenclature for describing various karyotypic

abnormalities. Refer to Gelehrter, Collins, and Ginsburg, 2nd ed., Chapter

8, for ideograms and chromosomal nomenclature. You will be responsible

for all of the material in this chapter.

Each chromosome consists of one double-stranded DNA molecule

running the length of the chromosome, along with histones and other proteins.The DNA is arranged in chromatin loops that have general gene expression

coordination. Two other distinct structures are essential, the centromere andthe telomere. The centromere is the site of attachment of the spindle fiber.

Without it the chromosome would not move in mitosis and meiosis, would belost from the nucleus, and would be degraded by cytoplasmic enzymes. The

telomeres are distinct structures at each end of the chromosome. They

maintain the structural integrity of the chromosomal DNA. When a telomere

is missing there is a strong tendency of the chromosomes to join with one

another, or with pieces of one another, causing abnormal gene expression and

aberrant chromosome structures.


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CHROMOSOME REPLICATION

Chromosome replication is different in humans than it is in bacteria,

although the method of DNA replication is the same. In bacteria there is one

origin of replication, but the polymerase is very fast. In humans thepolymerase copies only about 100 to 150 base pairs per second, but there are

20,000 to 100,000 origins of replication along the 46 chromosomes. Most of

these origins are functional in embryogenesis when divisions are occurringvery rapidly, but many fewer function in the adult. DNA synthesis begins at

several origins of replication along a chromosome and moves in eachdirection until it meets the replicated strands from the next origin.

Figure 5.

Chromosome replication.

The chromosomes replicate in a predetermined sequence in mitosis, with

each member of the homologous pair duplicating at the same time. Theexception in somatic cells, not germ line cells, is that one of the X

chromosomes of the female is always last of all the chromosomes to replicate.

X replication in female somatic cells does not occur simultaneously in each of

the homologs.

AUTOSOMAL ABNORMALITIES

Several autosomal abnormalities produce such serious changes in the

phenotype that they are not compatible with life. Any ploidy (extra copies ofall chromosomes, i.e., triploidy, tertaploidy, etc.) higher than diploid results in

early death in utero. Trisomy, an extra copy of a single chromosome, exceptfor chromosomes 13, 18, or 21, is not compatible with life. Trisomy 13 and

Trisomy 18 each lead to early death, usually in the neonatal period of

development if notin utero.


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Meiotic nondisjunction, the failure of the chromosomes to disjoin and

pass to opposite poles, in either the first or second meiotic division is the

major cause of chromosomal abnormalities. The greatest percentage of these(75%) occurs in oogenesis, where the probability of nondisjunction increaseswith maternal age. Almost 80% occur in the first meiotic division. To

understand a possible mechanism for these observations we need to review

oogenesis and spermatogenesis.

Figure 6. Events in spermatogenesis. (Note the timing.)

Spermatogenesis begins at puberty and continues on a regular pace

through the lifetime of the male, although spermatogonia do not divide as

rapidly during later life. Males in their eighth decade have been documentedfathers. The process from spermatogonium to mature sperm takes about 64

days, with each division evenly spaced at about 16 days, as shown in Figure 6.Spermatogenesis, with its many more cell divisions is more prone to single

gene mutations than is oogenesis. There may be as much as a four or five fold

increase in the mutation rate for some Mendelian traits in the sperm of older

men.

Oogenesis, on the other hand, is not associated with a higher mutation

rate for Mendelian diseases as maternal age increases. Increasing maternal ageis associated with a higher incidence of chromosomal abnormalities attributed

to nondisjunction. The reason for this association is evident from Figure 7below.


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Figure 7. Events in oogenesis.

All of the oocytes that are ever going to develop in the female are presentat birth and all have begun the first meiotic division before they are arrested inthe dictyotene state for from 12 to 40 years. Then with each menstrual cycle,

one oocyte begins to continue on through the first and second meioticdivisions. These divisions occur very rapidly. With an old mitotic apparatus it

is very possible that mistakes in chromosomal movement and cell division

will occur. In some ways spermatogenesis, with its liability for mutation, and

oogenesis, with its liability for chromosomal aberrations, may be thought of as

complementary, one protects against mutation while the other protects against

chromosomal abnormalities.

MEIOTIC NONDISJUNCTION

Nondisjunction, the failure of the chromosomes to disjoin and move to

opposite poles may affect as many as 25% of all ova and 2% of all sperm.Half of these abnormal gametes are nullisomy, half are disomy. Two copies of

a chromosome pass into the same gamete, leaving the other gamete as

nullisomy. At fertilization the zygote formed from the gamete with nullisomy

gets one copy of the chromosome from the gamete of the other parent and

becomes monosomic for that chromosome. Monosomy for an autosome is notcompatible with life. At fertilization, the zygote formed from the gamete with


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the two copies of the chromosome gets a third copy from the gamete of the

other parent and become trisomic. As discussed earlier, most do not survive toterm.

Down syndrome, or trisomy 21, is the classic example of a human disease

caused by autosomal nondisjunction where some, but not all, affected

individuals do survive. It occurs in about 1/800 live births, which means

around 5000 affected individuals are born each year in the United States. The

disease occurs in all races and nationalities. Approximately 95% of these 5000Down syndrome children are the result of meiotic nondisjunction. The error

occurred in first meiotic division in about 80% of these individuals; theremaining 20% occurred in second meiotic division. Errors in oogenesis

account for 75% of the births while about 25% are of paternal origin. For a

more complete discussion of Down syndrome, including the effects of

increasing maternal age, see Gelehrter, Collins, and Ginsburg, 2nd ed.,Chapter 8.

There are three other causes of Down syndrome besides simple trisomy21. Mitotic nondisjunction, isochrome formation, and Robertsonian

translocation can also produce Down syndrome.

MITOTIC NONDISJUNCTION (Mosaic)

A chimera is an individual that results from the fusing of two cell lines,from two zygotes, during development. Twins can, under extremely rare

circumstances, be chimeras. A mosaic individual is one who originated as a

single cell line and through some mitotic event develops two different cell

lines. Mitotic nondisjunction is one of the events that will produce a mosaic

individual. When mitotic nondisjunction of chromosome 21 occurs early indevelopment of a female, two new cell lines develop, 45, XX, -21 and 47, XX,

+21, in addition to the 46,XX founding cells. The monosomy 21 cell line doesnot survive. The karyotype of the mosaic female is written 46, XX/47,XX +

21. Of course there is an equal probability for the mosaic to arise in a male.

The severity of affected of mosaic individuals depends upon how early thenondisjunction occurred and what cell lines developed from those early

embryonic cells.

ROBERTSONIAN TRANSLOCATION

About 9% of Down syndrome children born to mothers who are less than30 years of age will be the result of Robertsonian translocation. Down

syndrome mothers under the age of 30 have a relatively low recurrence risk

for a second trisomy 21 if the first affected child resulted from either meioticor mitotic nondisjunction. However, the recurrence risk is much higher if the


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affected child was the result of a Robertsonian translocation. Robertsonian

translocations are limited to the acrocentric chromosomes, chromosomes 13,14, 15, 21, and 22. These chromosomes all have short arms, the parms, that

largely are made up of the genes for ribosomal RNA. These short arms are

usually called satellites. There are many copies of these genes and a personcan function quite well if several are lost. These satellites have a great deal of

homology from chromosome to chromosome, and they tend to associate

during interphase and mitotic division. Occasionally they will exchange parts,and the long arm, the qarm of one chromosome will become attached to

the qarm of another, with the loss of the two parms, or satellites. All that is

lost is a centromere and some ribosomal RNA genes. (Small chromosomal

structures get lost in mitosis because they do not attach to a spindle fiber.)

Two qarms are now attached (translocated) to the same centromere. This is

called a Robertsonian translocation. The formation of a Robertsonian

translocation is shown in Figure 8 below.

Figure

8. Robertsonian translocation.

There is no effect on the individual in which this mitotic event occurs. He

or she has a normal phenotype in all respects. Mitosis is unaffected. However,

if the translocation occurs in a cell that is destined to be in the germ line, thentrouble may arise when that cell tries to undergo meiosis. Pairing of

homologous chromosomes at metaphase of the first meiotic division may

create problems as described in Figure 9 below.


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Figure 9. Pairing of homologous chromosomes.

Figure 9 shows that pairing at the first meiotic division can occur threeways, with equal chances for all. When it occurs as shown in A, one

secondary oocyte or spermatocyte will get the 14q21q translocationchromosome and the other secondary oocyte or spermatocyte will get a

normal 14 and a normal 21. When fertilization occurs, with a normal 14 and a

normal 21 from the other parent, the zygotes formed from the gametes with

pairing as inA will be either 45, XX or XY, -14, -21, +t(14q21q) a

phenotypically normal balanced Robertsonian translocation carrier, or be a 46,

XX or XY normal individual. When pairing at first meiotic division is asshown in B, one secondary oocyte or spermatocyte will get chromosome 14

only (no chromosome 21) and the other secondary spermatocyte or oocytewill get chromosome 14q21q and chromosome 21. At fertilization, again the

zygote will get a normal 21 and a normal 14 from the other parent. When the

gamete from B that got only chromosome 14 unites with a normal gamete,

there is monosomy for chromosome 21. That results in very early embryonicdeath and spontaneous abortion. When the gamete from B that got the 14q21q

chromosome plus chromosome 21 unites with a normal gamete, one gets the

prober dose of necessary genetic information for chromosome 14 (14 from thenormal gamete and 14q of the translocation chromosome) but one has three

copies of the genetic information of chromosome 21(21 from the normal

gamete, and a 21 and a 21q from the translocation). This results in Down

syndrome. When, by chance the chromosomes line up as at C, both gametic

products are lethal early in development. One will get only chromosome 21and will be lacking a chromosome 14. Monosomy for chromosome 14 is

lethal. One will get a 14 and a 14q21q, resulting in a zygote that will betrisomic for chromosome 14. This trisomy is also lethal.

From a carrier of a Robertsonian translocation there are 6 types ofgametes, only three of which will produce a fetus capable of surviving to


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term. Of these three combinations who may survive, one should be normal,

one should be phenotypically normal but be a carrier of the translocation, andone should have Down syndrome. In actual practice, if the mother is the

carrier of the translocation only about 11% of the children have Down

syndrome, the remaining 89% non-Down syndrome children are equallydivided between normals and balanced translocation carriers. Trisomy 21

embryos do not survive as well as those with the normal amount of genetic

information. If the father is a carrier of the translocation, only about 2% of theoffspring will have Down syndrome, the remaining 98% being equally

divided between normal and balanced translocation carriers. Because

Robertsonian translocation is responsible for about 9% of the Down syndrome

children born to mothers under the age of 30, it is important to karyotype the

child to determine if the child is the result of a Robertsonian translocation or

simple meiotic nondisjunction. As one can see, the counseling of the parents is

entirely different. Robertsonian translocations are passed from generation togeneration, and with this type of inheritance Down syndrome may "run infamilies."

ISOCHROME FORMATION

Isochrome, or 21q21q, may result from a Robertsonian translocation

between the two 21 chromosomes during mitosis in the germ line, or it may

result from an improper mitotic division of the centromere, where the

centromere divides transversely rather than longitudinally. Either of these is arare event, but they do happen. When that happens it produces a karyotype,45, XX or XY (depending upon the sex of the individual) -21,-21,+I(21q).

Both q arms of chromosome 21 are attached to the same centromere. Ingametogenesis, the gametes from an isochrome 21 individual get either the

isochrome (21q21q) or they are missing chromosome 21 entirely. The zygotes

are then either monosomy 21, which is lethal, or they have a normal 21 and a

21q21q chromosome, resulting in Down syndrome. All of the viable offspring

of an isochrome 21 individual will have Down syndrome.

CHROMOSOMAL INHERITANCE

SEX CHROMOSOME ABNORMALITIES

n humans the normal female has two X chromosomes, while the

normal male has only one X chromosome. If a gene is on the Xchromosome, isn't it logical that there would be twice the gene product

in females than there is in males? This was a question that remained

unanswered for many years. From biochemical measurements there seemed to

be the roughly the same amount of gene product in both males and females.The phenomenon was called "dosage compensation." Somehow the gene


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knew to compensate for the sex of the individual, either make half as much

product if it found itself in a female or make twice as much product if it wasin a male. Dosage compensation was explained by the discoveries of Mary

Lyon.

LYON HYPOTHESIS

The Lyon hypothesis states that during early development, about the 100

cell stage in humans, one of the X chromosomes in a female gets turned off

and this is maintained in all descendant cells of the clone. Which of the two Xchromosomes gets turned off in each of the 100 cells is purely a random event

except where one of the X chromosomes is abnormal (deletion, insertion,inversion, etc.) An abnormal X is always turned off. However, if there is a

translocation between an X chromosome and an autosome, the normal X is

turned off and the translocation X remains active. In other words, undernormal conditions a female is a mosaic in each tissue derived from somatic

cells. If she is a heterozygote for a gene that is on the X chromosome and

controls an enzyme, say G6PD, on the average half of her cells will expressone allelic product of the G6PD gene and the other half of her cells will

express the other allelic product. No somatic cell will express both alleles.This explains the phenomenon of dosage compensation. Only one gene

product is produced in each cell of the female and only one gene product is

expressed in each cell of the male. However, for some reason both X

chromosomes remain active in female germ line cells.

BARR BODIES

The inactive X usually lies along the edge of the interphase nucleus in a

highly condensed state. It is always the last to replicate. In 1948, before the

discoveries of Lyon, Barr and Bertram found that in the interphase nucleus offemale cat neurons there were a significant number of cells that had one

"darkly staining body" lying along the edge of the nucleus, but they neverfound a "darkly staining body" in the neurons of male cats. Similar "darkly

staining bodies" are found in buccal epithelial cells of human females,

although they can usually be found in only 30% to 40% of the cells. Normal

males never express these "Barr bodies." In all cases, the number of Barr

bodies is one less than the number of X chromosomes in an individual. One

Barr body means the individual has two X chromosomes, two Barr bodiesmeans the individual has three X chromosomes, etc. We now know that the

"darkly staining" Barr body is the condensed, inactive X chromosome.

We also know that not all regions of the X chromosome in a female are

turned off. There is a blood group locus, Xg, which is near the end of the X

chromosome. Heterozygotes for this blood group express both allelic products


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on each erythrocyte. So there are exceptions to the Lyon hypothesis, but it

holds true as a general phenomenon.

Since X inactivation is a random event, sometimes more than half of the

cells will have, by chance, the same X inactivated. Rarely, but not as rarely as

mutation, so many cells of the heterozygote will share the same inactive X

that the female phenotype will appear to be that of the homozygote.

TURNER SYNDROME

Just as simple meiotic nondisjunction is the leading cause of autosomal

chromosome abnormalities, so is nondisjunction the leading cause of the X

and Y abnormalities. In autosomal abnormalities an increase in nondisjunctionwas associated with increasing maternal age. In sex chromosome

abnormalities, one additional source of nondisjunction can be identified, theproblem of X and Y pairing at first meiotic division in spermatogenesis. The

X and Y have homology only in a small region (called the pseudo autosomal

region) which lies near one end of each chromosome. Rather than pair along

their entire length, pairing (and possible recombination) occur only in this

small region. At first meiotic division in the male, pairing of X and Y looks

more like end to end pairing than longitudinal pairing. This undoubtably addsto the frequency of nondisjunction.

Turner syndrome (45,X) is the most frequent chromosomal abnormality.

It is found in more than 7% of all spontaneous abortions. As it affects onlyabout 1/2500 live female births, only about 2% of the recognized 45,X

embryos survive to term, 98% are lost. The nondisjunction that results in a

45,X female can occur at either meiotic division in either spermatogenesis or

oogenesis, but about 80% are the result of paternal nondisjunction. Turner

syndrome individuals can also result from early mitotic nondisjunction, beingmosaic 46,XX/45,X.

The phenotype of Turner syndrome individuals differs significantly fromthe normal female, even though the normal female has only one functioning X

chromosome in each cell. The events of embryogenesis during the time both

X chromosomes are functioning in the female must be critical, as well as those

few regions of the X chromosome that are not inactivated. Refer toGelehrter, Collins, and Ginsburg, 2nd ed., Chapter 8, for complete

descriptions of the phenotypes, and for further details on the sex

chromosome abnormalities, including fragile X.

KLINEFELTER SYNDROME

Klinefelter syndrome (47, XXY) occurs in about 1/850 male births. In thehuman, the presence of one Y chromosome produces male secondary sex


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characteristics in the absence of specific mutations for sex determining loci.

Since the child must get his Y chromosome from his father, thenondisjunction that produces a Klinefelter syndrome child could occur in

either meiotic division of the mother, but could only occur in the first meiotic

division in the father. If nondisjunction occurred in the father, the zygotewould have to get both an X and a Y chromosome in the same sperm. In

spermatogenesis this could only result from a mistake in first division. Second

meiotic division of spermatogenesis separates either the two X chromatidsinto different gametes or the two Y chromatids into different gametes.

XYY & XXX SYNDROMES

XYY syndrome occurs in about 1/1000 male births. It can only result

from nondisjunction in the second meiotic division of spermatogenesis. Even

though it affects only 1/1000 men, it is found in almost 1/50 males in prisonpopulations. Aggressive behavior and less intelligence than siblings are often

included in phenotypic descriptions of these 47,XYY individuals.

XXX syndrome (47,XXX) has such a normal phenotype that it is not

usually classified as a disease or even recognized unless there are reproductive

problems with spontaneous abortions. However, as a general rule, as thenumber of X chromosomes increases past the diploid state, mental

deficiencies increase.

NON-MEIOTIC CHROMOSOMALABNORMALITIES

> number of gross chromosomal changes can arise that results

either in altered gene control or in difficulties during meiosis or mitosis.

Inversions, non-Robertsonian translocations, and ring chromosomes all

produce, or have the potential for producing, altered phenotypes. Each of themis rare when compared to nondisjunction.

INVERSIONS

Inversions involve two chromosomal breaks and rejoining, with the

broken piece reincorporated in the opposite orientation from which it naturallyoccurs. When they include the centromere, they are called pericentric

inversions. When they do not include the centromere, they are called

paracentric inversions. Both types of inversions arise in mitotic cells. If they

arise in precursors of the gametes, they may produce abnormal genomes as

they progress through meiosis. Recombination between homologous

chromosomes is a necessary part of every normal meiosis. The probability fornondisjunction is greatly increased if there is no recombination. However,


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recombination between a chromosome with an inversion and its normalhomolog may result in two abnormal chromosomes being produced. The

results of a paracentric inversion going through meiosis, with a recombination

within the inversion, are shown in Figure 10. Of the four gametic products,

one is normal, one has the inversion, one has an acentric chromosome, and

one has a dicentric chromosome. The acentric chromosome cannot survive.The dicentric chromosome may be pulled apart during mitosis, with a randomloss or gain of genetic material.

Figure 10. Paracentric Inversion.

The results of a pericentric inversion going through meiosis, with a

recombination within the inversion is shown in figure 11. Again, fourdifferent gametic products are produced, one normal, one has the inversion,

and two have duplicated portions and deleted portions. The effect on the

phenotype is almost always deleterious, but the magnitude of the effect

depends upon the size of the duplications and deletions, and where they occur.


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Figure 11. Pericentric Inversion.

RING CHROMOSOMES

Ring chromosomes result from the loss of the telomeres, with a rejoining

of the ends of the same chromosome. When a telomere is lost there is a strongtendency for the chromosome to unite with a similar fragment lacking a

telomere. Ring chromosomes cause no problem until there is a sister

chromatid exchange. Sister chromatid exchange is a rather common mitotic

event. It can be detected in five or six chromosomes at each mitotic division

Since the two chromatids are identical in all respects, there is no gain or loss

of genetic material. However, when a sister chromatid exchange occurs in a

ring chromosome, a double chromatid is produce that is dicentric. Dicentricrings have the same problem going through mitosis as the dicentric

chromosomes of paracentric inversions. When the two centromeres line up on

opposite sides of the metaphase plate, they migrate to opposite poles, and the

chromosome is randomly broken, with loss or gain of genetic material. This

always produces a deleterious effect on the phenotype.

NON-ROBERTSONIAN TRANSLOCATIONS

Non-Robertsonian translocations, translocations between chromosomesother than those of the D or G groups, always have trouble going through first


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meiotic division. One half of the gametes of a person with a translocation will

involve duplications of some genetic material and deletions of other portionsof the chromosome. These are always deleterious, usually resulting in severely

affected individuals.

UNIPARENTAL DISOMY

Included in the discussion of Mendelian traits was a section on imprinting

in Prader-Willi syndrome and Angelman syndrome. 75% of the time these

diseases are caused by deletion within chromosome 15, more precisely 15q11-13. If the deletion occurs in the chromosome that came from the father (only

maternal genes present), Prader-Willi syndrome results. If the deletion occursin the chromosome that came from the mother(only paternal genes present),

Angelman syndrome results. The two syndromes are not at the same genetic

locus, but are controlled by genes that are within this small region ofchromosome 15. They have very different phenotypes.

Prader-Willi Angelman

Neonatal hypotonia &

developmental deficiency

Ataxia, seizures

Severe obesity Hyperactivity

Short stature Severe mental retardation

Hypogonadism Absence of speech

Mild to moderate mental

retardation

with learning disabilities

Inappropriate laughter

(Happy puppet syndrome)

Small hands and feet

In about 25% of Prader-Willi syndrome children, and about 2% of

Angelman syndrome children, the cause of the disease is not deletion butuniparental disomy, both copies of chromosome 15 came from one parent. In

the case of Prader-Willi syndrome both chromosomes came from the mother.

In the case of Angelman syndrome, both chromosomes came from the father.In about 1/30,000 conceptuses the zygote probably was a trisomy 15, a lethal

genetic condition, and early in mitotic development one chromosome 15 was

lost, restoring the embryo to the diploid state. If the nondisjunction thatproduced the trisomy 15 occurred in the mother, with the subsequent loss of

the paternal chromosome 15, Prader-Willi syndrome results. If the trisomyresulted from paternal nondisjunction with subsequent loss of maternal

chromosome 15, Angelman syndrome results. These two mechanisms,

deletion and uniparental disomy, account for virtually all of the Prader-Willi

syndrome patients. Angelman syndrome can also result from mutations within

the gene (or genes) that produce nonfunctional gene products.


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Although it is a rare event, uniparental disomy has been documented for

other autosomal chromosomes. Except for the unexpected expression of anautosomal recessive disease (heterozygote x homozygous normal mating), no

detectable phenotypic effect has been found.

MULTIFACTORIAL INHERITANCE

IMPORTANCE

ultifactorial inheritance is responsible for the greatest number of

individuals that will need special care or hospitalization because of

genetic diseases. Up to 10% of newborn children will express amultifactorial disease at some time in their life. Atopic reactions, diabetes,

cancer, spina bifida/anencephaly, pyloric stenosis, cleft lip, cleft palate,congenital hip dysplasia, club foot, and a host of other diseases all result from

multifactorial inheritance. Some of these diseases occur more frequently in

males. Others occur more frequently in females. Environmental factors as well

as genetic factors are involved.

REGRESSION TO THE MEAN

Multifactorial inheritance was first studied by Galton, a close relative of

Darwin and a contemporary of Mendel. Galton established the principle ofwhat he termed "regression to mediocrity." Mendel studied discontinuous

characters, green peas vs. yellow peas, tall vs. dwarf, etc. There was nooverlap of phenotype in Mendel's studies. Characters fit into one of two

classes. There was no blending in the heterozygote. On the other hand, Galton

studied the inheritance of continuous c

genetica humana beta

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