Human Genetics

Understanding Genetics with Family Trees

How do we use Mendel’s Observations about Dominant and Recessive Traits, Segregation and Independent Assortment to predict the inheritance of traits in humans?

Pedigree

- the family tree

- representation of the ancestry of an individual’s family.

- symbolic representations of family relationships and inheritance of a trait

Pedigree Analysis

Unaffected MaleUnaffected FemaleAffected male Affected female

Parents

Offspring

A numbering system is used to identify individuals

Individuals I1 and III1 express the unusual trait being studied

Rest have normal phenotypes

Proband - the first afflicted member of a family seeking medical attention.

- marked with the an arrow and the letter p

Pedigree

The family treerepresentation of the ancestry of an

individual’s family. symbolic representations of family

relationships and inheritance of a trait

Common Pedigree Symbols

Mode of Inheritance determined by inheritance pattern of mutant phenotype

Autosomal recessive Autosomal dominantX-linked recessiveX-linked dominantY-linkedmitochondrial

Most common

Criteria for an Autosomal Recessive Trait

Male and Female are both affectedAffected males and females can transmit

the trait, unless it causes death before reproductive age

Trait can skip generationsParents of affected are heterozygous or

have the trait and are homozygous.

Autosomal Recessive Inheritance of a Disease

Criteria for an Autosomal Dominant Trait

Male and Female are both affected. Can have male to male transmission.

Males and females transmit the trait with equal frequency

Successive generations are affectedTransmission stops if a generation arises

where no individual is affected.

Autosomal Dominant Inheritance

Dominant TraitDistal symphalangism is an autosomal dominant disorders characterized by fusion of the proximal or distal interphalangeal joints.

Comparison of autosomal dominant and autosomal recessive inheritance

NoYesAt least one parent of affected child must be affected?

YesNoTrait skips generations?

YesYesMales and females transmit the trait?

YesYesMales and females affected?

Autosomal recessive

Autosomal dominant

Trick Question Alert!

There is a tendency to believe that the dominant allele is more common than the recessive allele.

Sometimes that is true, but often it is not.Dominance and Recessive traits BOTH can

result from lack of expression of a gene and expression of an incorrect gene product. Recessive traits simply require two copies for the effect, while Dominance requires only one copy.

Some Human Mendelian Traits

There are only two alleles for each gene present in a normal diploid individual

Gene for blood group in humans has 3 allelesIA IB and IO

Many genes have more then two alleles- so the gene displays

multiple phenotypes

 

Codominance

Both alleles are expressed equally Heterozygotes fully express both allelesABO Blood groups

3 alleles 6 genotypes 4 phenotypes

Type AB blood - both the A and the B antigen are expressed on red blood cells

H structure: Mucopolysaccharide found on the RBC surface

3 alleles -- IA , IB , and IO

IA and IB are codominantIO is recessive

Type A blood can be IAIA or IAIO

Type B blood can be IBIB or IBIO

Type AB blood is IAIB - codominant stateType O blood is IOIO

Blood Types

Heterozygous phenotype is intermediate between the two parental homozygotes.

The heterozygous phenotype is typically intermediate to the homozygous phenotype.

Incomplete dominance

It takes 2 doses of the red allele to get redRR- red Rr – pink rr - white

Incomplete dominance

If you cross true breeding red and white snapdragons

F1 are all pink flowers

F2 - 1:2:1 red:pink:white

Independent Assortment in Humans: Albinism and Deafness

Lets look at some Pedigrees

Dimples

Autosomal dominant inheritance

Dimples

Brachydactyly

Autosomal dominant inheritanceWho could be carriers?

- Autosomal Recessive Disorder

- II1 and II2 must be carriers –Who else could be?

- at least 2 carriers in generation I

- but all could be carriers

Tay Sach’s Disease

Or, is it Incomplete Dominance?

The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of acidic fatty materials known as gangliosides.

Gangliosides are made and biodegraded rapidly in early life as the brain develops.

Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity.

Albinism

- Heterozygotes carry the recessive allele but exhibit the normal skin color (sometimes called wild type phenotype)

- Autosomal recessive

Pedigree Analysis

How do you evaluate a pedigree to determine the mode of inheritance of a particular trait? form a hypothesis as to how the trait is inherited test the pedigree for consistency with that

hypothesized mode of inheritance if consistent with the hypothesized mode of

inheritance, accept your hypothesis only when all other modes of inheritance can be been ruled out.

What type of inheritance does this trait have?

A.DominanceB.RecessiveC.Dominance or recessive- insufficient data to tell

What type of inheritance does this trait have?

A.DominanceB.RecessiveC.Dominance or recessive- insufficient data to tell

Predict inheritance of a dominant vs recessive?

Offspring 2 marries someone homozygous for the trait. What will their children be if the trait is recessive? Dominant- Heterozygote? Homozygote?

Statistical Genetic Predictions

What is the chance that Ellen’s child has a sickle cell anemia allele (a)?

Ellen Michael

?

Ellen and Michael’s parents must be carriers. A a

A

a

AA Aa

Aa aa

Ellen is not affected andcannot carry aa genotype

chance child inherits sickle cell allele = 1/2

Overall chance child carries sickle cell allele from Ellen = 2/3 x 1/2 = 1/3

chance Ellen is a carrier = 2/3

Ellen’s brother Michael hassickle cell anemia, an autosomal recessive disease.

most common – first cousins marriages

- share grandparents - risk passing on the same recessive alleles to offspring

Consanguinity

First Cousin Marriages

Over a billion people worldwide live in regions where 20%-50% of marriages are consanguineous - that is where the partners are descended from the same ancestor.

What is the risk really?

Dr. Bittles, Director for the Centre for Human Genetics in Perth, Australia

Collated data on infant mortality in children born within first-cousin marriages from around the world and found that the extra increased risk of death is 1.2%.

In terms of birth defects, he says, the risks rise from about 2% in the general population to 4% when the parents are closely related.

Data Quality isn’t Good

Born in Bradford Study 50% of births are Pakistani, and 70% of Pakistani

births in the study so far are from consanguineous marriages

150 genetic diseases identified, more than expected from other cities

British Paediatric Surveillance Unit Since 1997, 902 British children born with

neurodegenerative conditions 8% of those were in Bradford which only has 1% of

the population.

Ptolemy Dynasty 323 BC to 30 BC

Preferred marriage was brother/sister

Why is so much inbreeding not fatal?

It could have an effect, but the early miscarriages and diminished fertility and infant deaths weren’t recorded.

What are the proposed solutions and ethical considerations?

Make first cousin marriage illegal? This is a strong cultural preference in many

cultures and could be discriminatory

Test pregnancies for genetic defects and have selective abortions? This requires legal abortions and screening that

is as early as possible

Provide parental screening and counseling? This could lead to prejudice against carriers

There are very few life guards at the gene pool in WV

Human Genetics Testing Staff are certified by: The American Board of

Medical Genetics The American Board of

Genetic Counseling The American Board of

Pathology: Molecular Genetic Pathology

Sharon L Wenger, PhD West Virginia University

Dept Pathology