Pedigree Analysis

Classical Genetics

• Mendelian inheritance describes inheritance patterns that obey two laws– Law of segregation – Law of independent assortment

• Simple Mendelian inheritance involves – A single gene with two different alleles– Alleles display a simple dominant/recessive

relationship

Wild-type (dominant) allele Mutant (recessive) allelePurple flowers White flowers

Axial flowers Terminal flowers

Yellow seeds Green seeds

Round seeds Wrinkled seeds

Smooth pods Constricted pods

Green pods Yellow pods

Tall plants plants

• Consider, for example, the traits that Mendel studied

• Another example is from Drosophila

Wild-type (dominant) allele Mutant (recessive) alleleRed eyes White eyes

Normal wings Miniature wings

• Human genetic diseases caused by recessive mutant alleles– The mutant alleles do not produce fully

functional proteins

Lethal Alleles• Essential genes are those that are

absolutely required for survival– The absence of their protein product leads to a

lethal phenotype• It is estimated that about 1/3 of all genes are

essential for survival

• Nonessential genes are those not absolutely required for survival

• A lethal allele is one that has the potential to cause the death of an organism – These alleles are typically the result of

mutations in essential genes– usually recessive, but can be dominant

• Many lethal alleles prevent cell division

• Some lethal allele exert their effect later in life– Huntington disease

• Characterized by progressive degeneration of the nervous system, dementia and early death

• The age of onset of the disease is usually between 30 to 50

• Conditional lethal alleles may kill an organism only when certain environmental conditions prevail – Temperature-sensitive (ts) lethals

• A developing Drosophila larva may be killed at 30 C• But it will survive if grown at 22 C

Lethal Alleles

• Every gene carries information telling the body how to make a particular protein. – Adult cells have two copies of each gene. – If one copy of the gene doesn’t work, the cell

has a backup.

• New versions of genes can be produced by mutations– These new alleles can produce proteins that

either• Do not work• Or do something they’re not supposed to

• Thus any condition associated with this is referred to as a genetic disease

• Cystic fibrosis (CF)– A recessive disorder of humans– About 3% of caucasians are carriers – The gene encodes a protein called the cystic

fibrosis transmembrane conductance regulator (CFTR)• The CFTR protein regulates ion transport across

cell membranes

– The mutant allele creates an altered CFTR protein that ultimately causes ion imbalance• This leads to abnormalities in the pancreas, skin,

intestine, sweat glands and lungs

Example: Cystic fibrosisThe cell membranes of the cells lining the lungs and air passages contain CF membrane proteins

Cell membrane CF membrane proteins

The CF protein pumps chloride ions from one side of the membrane to the other

Cl-

Cl-Cl-

Cl-

The CF protein produces a higher concentration of chloride ions on one side of the membrane than the other

…osmosis.

H2OH2O

H2O

Cell membrane

Cl-

Cl-

Cl-

Cl-

Cl-Cl- Cl-

Water molecules follow the chloride ions across the semi-permeable cell membranes by…

H2OH2O

H2O

The body uses the CF chloride pump to move water into secretions like the mucus found in the trachea and sweat.

If your cells cannot make working chloride pumps, your mucus becomes too thick and sticky due to lack of water

However, to make a functioning chloride pump, each cell only needs one good copy of the gene for it.

So, cystic fibrosis is recessive

Cc

Defective gene produces non-working chloride pump

Healthy gene produces working chloride pump

This individual does not suffer from cystic fibrosis,but is a carrier

Cl-Cl-

Cl-Cl-Cl-

Cl-

Cl-

Cl-Cl-

Cl- Cl-

c c

This individual will suffer from cystic fibrosis

REMEMBER: Genes do NOT exist to cause disease…

… defective genes cause disease

Cl-Cl-

Cl-Cl-Cl-

Neither copy of the gene carried by this individual can produce a working chloride pump

Cl-Cl-

Cl-Cl-Cl-

Pedigree Analysis

• In the study of human traits, there are not controlled parental crosses

• Rely on information from family trees or pedigrees

• Pedigree analysis is used to determine the pattern of inheritance of traits in humans

Figure 2.10

Pedigree Symbols

Pedigree Analysis

• Pedigree analysis is commonly used to determine the inheritance pattern of human genetic diseases

• Genes that play a role in disease may exist as– A normal allele – A mutant allele that causes disease symptoms

• Disease that follow a simple Mendelian pattern of inheritance can be– Dominant – Recessive

• A recessive pattern of inheritance makes two important predictions– 1. Two normal heterozygous individuals will

have, on average, 25% of their offspring affected

– 2. Two affected individuals will produce 100% affected offspring

• A dominant pattern of inheritance predicts that– An affected individual will have inherited the

gene from at least one affected parent– Alternatively, the disease may have been

the result of a new mutation that occurred during gamete formation

Figure 2.10