Linked Genes, Sex Linkage and Pedigrees

Chapter 15

Pages333 - 354

Linked Genes 1Genes on the same chromosome are said to be linked. They are inherited together as a unit and do not undergo independent assortment.

Linkage can alter expected genotype and phenotype ratios in the offspring.

In this example, only two types of gamete are produced instead ofthe expected four kinds if the geneswere assorted independently.

Genes A and B control different traits and are on the same chromosome

aBaBGametes AbAb

Meiosis

One homologous pair of chromosomes

Oocyte

Linked Genes 2

Genes located on the same chromosome are said to be linked (e.g. genes A and B).

Linked genes tend to be inherited together.

Linkage results in fewer genetic combinations of alleles in offspring (compared to genes on separate chromosomes).

In describing linkage, the appropriate notation shows a horizontal line separating linkage groups.

Chromosome pair before replication

Chromosomes after replication

Parent 2 (2N)Parent 1 (2N)

LinkedLinked

ABab

abab

Line indicates linkage

Two genes are linked when they are on the same chromosome

Linked Genes 3

The inheritance patterns involving linked genes do not follow expected Mendelian ratios.

In this example of linked genes, only two kinds of genotype combinations occur in the offspring.

Without linkage, the same parents would provide four possible genotypes: AaBb, Aabb, aaBb, aabb.

Chromosomes after replication

X

Possible offspringOnly two genotype

combinations occur

AaBb AaBb aabb aabb

Meiosis

Only one

gamete from

each replicated

chromosome is

shown

Gametes (N)

RecombinationRecombination refers to the exchange of alleles between homologous chromosomes as a result of crossing over between linked genes.

Recombination results in new combinations of parental characteristics in the offspring.These offspring are called recombinants.

Recombination between allelesof parental linkage groups isindicated by the appearance of recombinants in the offspring,although not in the proportionsthat would be expected withindependent assortment.

Recombinant

offspring

Non-recombinant

offspring

Off

spri

ng

aaBbAabbaabbAaBb

Gam

etes

(N

)Meiosis

AB Ab aB ab ab ab ab ab

Before replication

AB

ab

ab

ab

Parent 2 (2N)Parent 1 (2N)

Linked genes

Crossing over has occurred

After replicationX

Autosomal & Sex-Linked GenesGenes on one or other of the sex chromosomes produce inheritance patterns different from that shown by autosomes:

Autosomal Genes

1. All individuals carry two alleles of each gene

2. Dominance operates in both males and females

3. Reciprocal crosses produce the same results

4. Alleles passed equally to male and female offspring

Sex-Linked Genes

1. Males carry only one allele

of each gene (hemizygous)

2. Dominance operates in females only.

3. Reciprocal crosses produce different results.

4. ‘Criss-cross’ inheritance pattern: father to daughter to grandson, etc

Sex Linkage

Sex linkage refers to the phenotypic expression of an allele that is dependent on the sex of theindividual and is directly tied to the sex chromosomes.

Most sex linked genes are present on the X chromosome (X-linkage) and have no corresponding allele on the smaller male chromosome.

In some cases, a phenotypic trait is determined by an allele on the Y chromosome. Because the Y chromosome is small and does not contain many genes, few traits are Y-linked and Y-linked diseases are rare.

Note the size differences between the X and Y chromosomes. The Y lacks alleles for many of the genes present on the X.

X

Y

Affected son

X Y

Sex LinkageSex-linked traits show a distinct pattern of inheritance.

Fathers pass sex-linked alleles to all their daughters but not to their sons.

Mothers can pass sex-linked alleles to both sons and daughters.

In females, sex-linked recessive traits will be expressed only in the homozygous condition.

In contrast, any male receiving the recessive allele from his mother will express the trait.

Carrier daught

er

XX

Unaffected

daughter

XX

Unaffected son

YX

Carrier

mother

X XX Y

Unaffected

father

Pedigree AnalysisPedigree analysis is a way of illustrating inheritance patterns. It is a good way to follow the inheritance of genetic disorders through generations.

Sex

unknown

Generati

ons

I, II, III

Children (in birth

order)

1, 2, 3

Non-

identical

twins

Died in

infancy

Carrier

(heterozyg

ote)

Affected male

Affected

female

Normal male

Normal female

Identic

al

twins

Symbols are used to represent males, females etc. For traits of interest, symbols can be shaded to indicate individuals carrying the trait.

Individuals are designated by their generation number and then their order number in that generation.

Sex Linked Recessive InheritanceFor a recessive trait controlled by a gene on the X chromosome, the features of inheritance can be illustrated with the standard symbols used on pedigree charts. Note that:

More males than females express the trait.

Carrier females do not show the trait but pass it to sons.

All daughters of affected males will at least be carriers of the trait.

Affected maleUnaffected female

Carrier

Famously, Queen Victoria was a carrier of the allele for hemophilia, passing it to one of her sons and, through her daughters, to the royal families of Prussia, Russia, and Spain.

Sex Linked Dominant Inheritance

Sex-linked dominant inheritance is rarer because all daughters of affected males will be affected (the heterozygous condition is not a carrier).

Sex-linked dominant traits are never passed from father to son.

Affected females produce 50% normal and 50% affected offspring.

Unaffected female

Affected male

Some X-linked dominant conditions, such as

Aicardi syndrome, are lethal to boys. They are

usually seen only in girls but may be seen in

males with Klinefelter syndrome (XXY)

Sex Linkage in HumansA rare form of rickets in humans is a sex-linked dominant trait. It is determined by a dominant allele of a gene on the X chromosome.

This condition is not treatable with vitamin D therapy.

A typical inheritance pattern is shown. XR indicates affected by rickets.

Nor

mal

wom

an

Affect

ed

maleParents X

Genetic Counseling

In the example of the sex-linked dominant form of rickets, the ratios of affected children can be determined if the phenotype and genotype of each parent is known.

In this case, the prospective parents would be advised that there is a 50% chance of having an affected child. Only girls would be at risk.

Possible

fertilizatio

ns

Children

Affect

ed

femal

e

Nor

mal

male

Affect

ed

femal

e

Normal

male

XXRXY XYXXR

Gametes YXRXX

XRYXX

These are inherited disorders caused by dominant alleles on autosomes. Dominant conditions are evident both in heterozygotes and in homozygous dominant individuals. Examples include:

Huntington disease

Autosomal Dominant Disorders

Autosomal Dominant Pattern• An idealised pattern of

inheritance of an autosomal dominant trait includes the following features:• both males and females

can be affected• all affected individuals have

at least one affected parent• transmission can be from

fathers to daughters and sons, or from mothers to daughters and sons

• once the trait disappears from a branch of the pedigree, it does not reappear

• in a large sample, approximately equal numbers of each sex will be affected.

Autosomal Recessive Disorders

(Pho

to: U

K C

ystic

Fib

rosi

s G

ene

The

rapy

Con

sort

ium

)

Inherited disorders caused by recessive alleles on autosomes. Recessive conditions are evident only in homozygous recessive genotypes. Eg. Cystic fibrosis.

The pedigree for albinism (lack of pigment in the hair, skin and eyes) is inherited as an autosomal recessive trait.

The trait is not sex linked and is shown by both males and females. The affected female in the third generation has phenotypically normal parents.

All generation II offspringare carriers for the albinoallele.

III-2 is an albino girl whosepaternal grandmother andmaternal grandfather arealso albinos.

All her other relatives are phenotypically normal.

• An idealised pattern of inheritance of an autosomal recessive trait includes the following features:

• both males and females can be affected

• two unaffected parents can have an affected child

• all the children of two persons with the condition must also show the condition

• the trait may disappear from a branch of the pedigree, but reappear in later generations

• over a large number of pedigrees, there are approximately equal numbers of affected females and males.

Hemophilia is an X-linked disorder in which blood clotting time is prolonged.

Women who are heterozygotes are carriers for the recessive allele but do not have hemophilia. They can pass the allele to their sons (XY) who will express the recessive allele and have hemophilia.

In the first generation, the femaleof the affected family is a carrierfor the hemophilia allele.

Two of the offspring of the affectedfamily also carry the allele; the maleis affected and the female is a carrier.

Offspring of the female carrier andan unaffected male can be unaffected,carrier females, or affected males.

Inheritance of X-LinkedRecessive Traits

X linked Recessive Pattern• An idealised pattern of inheritance of an X-

linked recessive trait includes the following features:

• all the sons of a female with the trait are affected

• all the daughters of a male with the trait will be carriers of the trait and will not show the trait; the trait can appear in their sons

• none of the sons of a male with the trait and an unaffected female will show the trait, unless the mother is a carrier

• all children of two individuals with the trait will also show the trait

• in a large sample, more males than females show the trait.

In this rare pattern of inheritance, all the daughters of affected males will be affected and more females than males will show the trait.

An affected male must always have an affected mother.

The inheritance of a rareform of rickets follows thisinheritance pattern.

The male I-2 is affected and allhis daughters II-2, II-3, and II-4are affected.

The affected female II-4 canproduce affected offspring ofboth sexes (III-2, III-3).

Inheritance of X-LinkedDominant Traits

X linked Dominant Pattern• An idealised pattern of inheritance of an X-linked

dominant trait includes the following features:

• a male with the trait passes it on to all his daughters

and none of his sons

• a female with the trait may pass it on to both her

daughters and her sons

• every affected person has at least one parent with the

trait

• if the trait disappears from a branch of the pedigree, it

does not reappear

• over a large number of pedigrees, there are more

affected females than males

Examples include:Vitamin D

resistant rickets

Y-linkage

• The Y chromosome has fewer genes and most are involved in male sex

determination and fertility.

• So there are fewer Y-linked genetic disorders.

• Y-linked conditions:

- Hairy ears

- Azoospermia – almost

nil sperm

Is the condition observed in each generation of a family in which it occurs?

Is the condition mainly in males?

If daughters have the condition does their father also have it?

Do males with the condition who mate with a normal female have all daughters, but no sons with the condition?

Do only males have condition, passing it from father to son?

NO YES

ON

NO

YESAutosomalrecessive

Sex-linkedrecessive

NO

YESAutosomaldominant

Sex-linkeddominant

YES

Y linkage

Types of variation• Genetic traits influenced by a single gene usually only have

two or three possible phenotypes.

(EG. Positive or negative blood factor, right or left handed, ear

lobe shape, dimpled chin, hand clasp)

• The population is said to show discontinuous variation for the

trait.

• Data would look like this graph

no in-between variations

just one or the other. 20

0.2

0.4

0.6

0.8

1

1.2 Rh factor

% of popu-lation

• Discontinuous variation can be influenced by more than one

gene.

• For example in budgerigars feather colour is influenced by

three genes that produce seven colours.

• Each colour is distinguishable from the others so they are still

discontinuously variable.

2 3 4 5 6 70

5

10

15

20

25

30

35Feather colour in Budgerigars

% of popula-tion

• When a large number of genes (called polygenic) influence a

phenotype then the population will show continuous

variation.

• Individual phenotypes are impossible to distinguish.

• Examples:

- Height and mass in humans.

- Milk production in cows.

0

5

10

15

20

25

30

35

Height

% of popula-tion