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 Male Unaffected Female Affected 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 tree  representation 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 dominant  X-linked recessive  X-linked dominant  Y-linked  mitochondrial Most common

Criteria for an Autosomal Recessive Trait  Male and Female are both affected  Affected males and females can transmit the trait, unless it causes death before reproductive age  Trait can skip generations  Parents 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 affected  Transmission stops if a generation arises where no individual is affected.

Autosomal Dominant Inheritance

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

Comparison of autosomal dominant and autosomal recessive inheritance NoYes At least one parent of affected child must be affected? YesNoTrait skips generations? Yes Males and females transmit the trait? Yes Males 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 alleles I A I B and I O Many genes have more then two alleles- so the gene displays multiple phenotypes

Codominance  Both alleles are expressed equally  Heterozygotes fully express both alleles  ABO 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 --I A, I B, and I O I A and I B are codominant I O is recessive Type A blood can be I A I A or I A I O Type B blood can be I B I B or I B I O Type AB blood is I A I B - codominant state Type O blood is I O I O 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 red RR- redRr – 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 inheritance Who could be carriers?

- A utosomal 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.Dominance B.Recessive C.Dominance or recessive- insufficient data to tell

What type of inheritance does this trait have? A.Dominance B.Recessive C.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)? EllenMichael ? Ellen and Michael’s parents must be carriers. A a AaAa AAAa aa Ellen is not affected and cannot 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 has sickle 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