The Inheritance of Single-Gene Differences

Human pedigree analysis and organelle inheritance

Genotype and

Phenotype

What is the difference?

Review Words} Characteristics – are the category of a trait –

} Example – eye color, height, likes/dislikes

} Traits – the physical, social, and emotional qualities of an organism} Example – blue eyes, tall, hates carrots

} Dominant Trait – when a majority of an organism shows the trait. } Example – most pea plants show as tall

} Recessive Trait – when a minority of an organism shows the trait.} Example – few pea plants show as short

} Alleles – all the possible choices for a characteristic} Example – eye color – blue, brown, gray, green

Genotype

}How the genes code for a specific trait.

} If the trait is dominant it uses a capital letter} Example – Tall (T)

} If the trait is recessive it uses the same letter but lower case} Example – short (t)

}Genotypes always have two letters –one for dad and one for mom

Types of genotype

´Purebred (homozygous) dominant – the genes only have the dominant trait in its code.´Example – Dominant Tall -- TT

´Purebred (homozygous) recessive – the genes only have the recessive trait in its code.´Example – Recessive short – tt

´Hybrid (heterozygous) – the genes are mixed code for that trait.´Example – hybrid Tall -- Tt

Phenotype

´The outward appearance of the trait.

´How an organism looks´How an organism acts´How an organism feels

Tricks to remembering the difference between Genotype and Phenotype

´Genotype – deals with GENE CODE.´Phenotype – deals with looks you can take a PHOTO with.

Pedigrees analysis´Analysis of inheritance in human families´Typically small number of offspring´ -> Mendelian ratios rarely observed´Allow inferences concerning genotypes

and predictions concerning phenotypes of offspring (genetic counseling)

unaffectedmale

unaffectedfemale

affectedmale

affectedfemale

Most common signs and symbols used in pedigree

analysis

Categories of inheritance ´Autosomal recessive

´e.g., PKU, Tay-Sachs, albinism´Autosomal dominant

´e.g., Huntington’s Disease´X-linked recessive

´e.g., color-blindness, hemophilia´X-linked dominant

´e.g., hypophosphatemia´Y-linked´Organelle

Pedigree analysis: case 1

´ Two children, one of each sex, show the trait but trait was not shown in the parents

´ Conclusions:´ must be autosomal recessive trait (example: PKU)´ parents must be heterozygous (Pp)´ 2/3 chance for each child to be heterozygous (Pp)´ 1/3 chance for each child to be homozygous (PP)

P/p P/p

pppp PP or Pp PP or Pp PP or Pp

An autosomal recessive disorder is revealed by the appearance of the phenotype in both male and female progeny of unaffected individuals, who may be inferred to be heterozygous carriers

Autosomal recessive inheritance in pedigrees

Pedigrees: Case 2

A/a a/a

a/a a/aA/a A/aA/a

A/a A/a A/a

a/aa/aa/a

a/a a/a a/a a/a a/a a/a

Autosomal dominant (AD) disorders are those in which both heterozygotes and homozygousdominant individuals show the abnormal phenotype.

One copy of the mutant gene is sufficient for expression of the abnormal phenotype = haplo-insufficiency (Note: In fact, in some AD diseases the homozygous genotype is incompatible with life)

Autosomal dominant disorders

- Every individual developing the disease must have an affected parent (except in cases of de novo mutations)

- Males and females are equally likely to inherit the allele and be affected (autosomal disorder)

- Recurrence risk (the probability that a genetic disorder that is present in a patient will recur in another member of the family) for each child of an affected parent is 1⁄2. If one parent is a heterozygote for a particular gene, their offspring will either inherit the gene or they will not, with each outcome equally likely.

- Normal siblings of affected individuals cannot pass the trait on to their offspring. If an affected individual’s siblings are not affected, they do not carry the mutation and cannot pass it on to their own offspring (thus a dominant mutant allele should be lost rapidly from the population if it affects greatly the fitness of the carrier).

Characteristics of pedigrees for AD disorders:

Typical pedigree for AD disorder

A/a a/a

a/a a/aA/a A/aA/a

A/a A/a A/a

a/aa/aa/a

a/a a/a a/a a/a a/a a/a

- Half the people in the Venezuelan village of Barranquitas are affected

- A large-scale pedigree analysis was conducted including 10,000 people

- Example for one particular family:

Huntington’s disease: an example of AD disorder

Huntington’s disease: an example of AD disorder- Neurological disorder causing convulsions, paralysis, loss of memory and eventually death

- Affected people do not show symptoms until their 30s to 50s (so they may not know that they are affected before they have children)

- Caused by programmed death of brain cells

- Exact reasons why brain cells die are unknown but HD gene has been identified on Chr4. He encodes a protein of unknown function (huntingtin).

- Disease caused by extension of CAG triplet within coding sequence of HD gene, resulting in a protein with a longer stretch of glutamin residues

- It is the presence of this abnormal form, and not the absence of the normal form, that causes harm in HD. This explains why the disease is dominant and why two copies of the defective gene do not cause a more serious case than inheritance from only one parent.

Pedigrees: Case 3

´ If allele associated with trait is very rare, this pedigree is most consistent with X-linked recessive inheritance

´ A single affected female would indicate autosomal (because for X-linked trait, homozygous females can only result from parents both carrying the recessive allele so affected female are very, very rare)

XAXaXAY

XaY XAXa or

XAXA? XAY XAXa or

XAXA ?XAY

Pedigrees: Case 3 XAXaXAY

XaY Must beXAXa XAY XAXa or

XAXA XAY

XAYXAYXaY XaY XaYXAXa or

XAXA

are characterized by the following pedigree pattern:

(1) Many more males than females develop the disease (ie. show the phenotype)

(2) None of the offspring of an affected male are affected, but all of its daughters must be heterozygous carriers (half the sons born to these carrier daughters are affected)

X-linked recessive disorders

Pedigree of an X-linked recessive disorder

Son non affected

Daughter carrier

1/2 grandsons affected

Father affected

are characterized by the following pedigree pattern:

(1) Affected males pass the condition on to all their daughters but none of their sons (unlike dominant autosomal disorders where daugthers and sons have an equal probability to inherit the disease)

(2) Affected females are mostly heterozygotes. When married to unaffected males, they pass the condition on to 1/2 of their sons and 1/2 of their daughters (same pattern than for autosomal dominant disorder)

X-linked dominant disorders

Note: X-linked dominant disorder are rare traits in human (ex: hypophosphatemia: low levels of inorganic phosphate in the blood.) Diagnose is complicated by the process of X inactivation in females.

Case 4: X-linked dominant disorders

Organelle inheritance

´ Mitochondria and chloroplasts´ small number of genes on circular chromosome´ mostly inherited through maternal lineage via egg cytoplasm´ organelle DNA are circular, and furthermore DNA circles can be

seen in organelle preparations under the electron microscope.´ organelle chromosomes are present in many copies per cell, often

in the hundreds or thousands´ In human there can be from 2 -

10 mtDNA molecules/mitochondrion´ 22 human mitochondrial tRNAs are shown on the maps

´ Examples´ white green variegation in plants´ Maternal inheritance also shown to primarily occur in humans but

some controversy on possible paternal contributions as well (and possible recombination between maternal and paternal mitochondrial genomes)

THE STEPS WHEN INTERPRETING A PEDIGREE CHART

§ Determine if the pedigree chart shows an autosomal or X-linked disease.

§ If most of the males in the pedigree are affected, then the disorder is X-linked

§ If it is a 50/50 ratio between men and women the disorder is autosomal.

INTERPRETING A PEDIGREE

§

CHARTDetermine whether the disorder is dominant or recessive.

§ If the disorder is dominant, one of the parents must have the disorder.

§ If the disorder is recessive, neither parent has to have the disorder because they can be heterozygous.

Pedigree showing transmission and expression of a mitochondrial trait. Note that transmission occurs only through females.

Rules of InheritanceAutosomal Recessive

•Appears in both sexes with equal frequency••

•

Trait tend to skip generations Affected offspring are usually born to

unaffected parentsWhen both parents are hetrozygout,

approx. 1/4 of the progeny will be affected• Appears more frequently among the

children of consanguine marriages

Rules of Inheritance

•••

Autosomal DominantAppears in both sexes with equal frequency Both sexes transmit the trait to their offspring Does not skip generations

• Affected offspring must have an affected parent unless they posses a new mutation

•When one parent is affected (het.) and the other parent is unaffected, approx. 1/2 of the offspringwill be affected

• Unaffected parents do not transmit the trait

Rules of Inheritance

•

•

X-Linked DominantBoth males and females are affected; often more

females than males are affectedDoes not skip generations.

••

Affected sons must have an affected mother; affected daughters must have either an affected mother or an affected father

• Affected fathers will pass the trait on to all theirdaughters

• Affected mothers if heterozygous will pass the trait on to 1/2 of their sons and 1/2 of their

daughters

Rules of InheritanceX-Linked Recessive

´More males than females are affected Affected sons are usually born to unaffected mothers, thus the trait skips generations Approximately 1/2 of carrier mothers’ sons are affected´ It is never passed from father to son´All daughters of affected fathers arecarriers

Rules of Inheritance

••

MitochondrialTrait is inherited from mother only

All children of a mother are at risk to beaffected or carriers

•••

Y-Linked Dominant Only males are affected

It is passed from father to all sons It does not skip generations

Example 1

X-linked recessive Hemophilia

Only males are affected and sons do not share the phenotype of their father - Thus X-linked

Expression of hemophilia skips generations: RECESSIVE

Example 2

X-Linked Dominant Every Generation: Dominant

Father passes on to only daughters Mothers passes on to 1/2 of offspring

Example 3

Autosomal RecessiveAffected individual from

unaffected parents

Example 4

Autosomal recessive Expressed in both sexes at approximately

equal frequency: AUTOSOMALNot expressed Autosomal Recessive in every

Example 5

Autosomal Dominant In every generation:

DOMINANTEqual in Males and Females:

Example 6

Autosomal DominantAppears equally In both sexes so autosomal

In every generation so

Example 7

Y-LinkedOnly males are affected All sons of

affected father

Example 8

X-Linked Dominant

Every generation: DOMINANT

Daughters of affected males are affected

Example 9

Autosomal DominantIn every generation: DOMINANT

Both Male and female affected:

Example 10

Mitochondrial All children at risk

Father doesn’t pass it along to any children

Example 11

Autosomal Recessive

Consanguinity

Example 12

Mitochondrial Inheritance

Example 13

Autosomal dominantIn every generation: DOMINANT In males and females: Autosomal

Example 14

Mitochondrial InheritanceFathers don’t transmit, just mothers

Example 15

X-linked Recessive