Difficulty: Intermediate | Prerequisites: Parts 1 and 2 of these notes (Mendel's laws, probability rules, dominance patterns).
Section 14.4 applies everything from the earlier sections to human genetics. Because controlled crosses are not possible in humans, geneticists use pedigree analysis to trace traits through families. This section covers how to read and construct pedigrees, how to calculate the probability of a child inheriting a given trait, and the major categories of human genetic disorders (recessive, dominant, and multifactorial). It also introduces genetic testing and counselling, including fetal and newborn screening methods.
Pedigrees let you track dominant and recessive traits through human families and calculate offspring probabilities using Mendel's rules. Recessive disorders (cystic fibrosis, sickle-cell disease, Tay-Sachs) require two copies of the disease allele and are often carried silently by heterozygous parents. Dominant disorders (Huntington's disease, achondroplasia) need only one copy. Many common diseases are multifactorial, meaning both genes and environment contribute. Genetic counselling, carrier tests, and prenatal screening help families assess risk.
Pedigree
A family tree diagram showing the inheritance of a trait across generations. Squares represent males, circles represent females, filled symbols indicate individuals expressing the trait.
Carrier
A heterozygous individual who carries one copy of a recessive disease allele without showing symptoms. In simple terms, they can pass the allele to offspring without being affected themselves.
Consanguineous mating
Mating between close relatives. This increases the probability that both parents carry the same recessive allele inherited from a shared ancestor, raising the chance of homozygous recessive offspring.
Cystic fibrosis (CF)
The most common lethal genetic disease in people of European descent (about 1 in 2,500). A recessive disorder caused by a defective chloride-channel gene, leading to thick, sticky mucus in the lungs, pancreas, and other organs.
Sickle-cell disease
The most common inherited disorder among people of African descent (about 1 in 400). Caused by a single amino acid substitution in haemoglobin. Recessive at the organismal level; codominant at the molecular level. Carriers (sickle-cell trait) have some resistance to malaria.
Tay-Sachs disease
A recessive disorder in which lipids accumulate in brain cells due to a missing enzyme. Fatal in early childhood. Carriers can be identified by blood tests measuring enzyme activity levels.
Huntington's disease
A dominant, late-onset, lethal neurological disorder. Symptoms typically appear between ages 35 and 45. Caused by an allele on chromosome 4; a genetic test can detect the allele before symptoms appear.
Achondroplasia
A form of dwarfism caused by a dominant allele. Heterozygous individuals show the dwarf phenotype; homozygous dominant is usually lethal. Occurs in about 1 in 25,000 births.
Amniocentesis
A prenatal diagnostic procedure performed from the 15th week of pregnancy. A needle extracts amniotic fluid; the fetal cells in the fluid are cultured and tested for genetic disorders.
Chorionic villus sampling (CVS)
A prenatal diagnostic procedure that can be performed as early as the 10th week of pregnancy. A tube extracts a small sample of placental tissue (chorionic villi), which shares the fetus's genotype.
Phenylketonuria (PKU)
A recessive disorder (about 1 in 10,000 to 15,000 births in the US) in which the body cannot metabolise the amino acid phenylalanine. If detected at birth, a low-phenylalanine diet prevents intellectual disability.
Genetic counselling
Professional guidance that helps prospective parents assess the risk of having a child with a genetic disorder, using pedigree analysis, probability calculations, and carrier testing.
Squares = males; circles = females; horizontal line connecting them = mating
Filled (shaded) symbols = individuals who express the trait; open symbols = unaffected
Offspring are listed below their parents in birth order (first-born on the left)
Dominant trait pattern: the trait appears in every generation. If both parents show the trait, an unaffected child can still appear (that child is homozygous recessive). If it were recessive, two unaffected parents could not have an affected child.
Recessive trait pattern: the trait can skip generations. Two unaffected parents can produce an affected child (both are carriers). If the trait were dominant, at least one parent would have to show it.
Widow's peak (W) is dominant over straight hairline (w)
Grandparents with widow's peaks who have some offspring without it must be Ww (heterozygous carriers)
A child with a widow's peak from two Ww parents could be WW or Ww
A child without a widow's peak must be ww
The inability to taste PTC is recessive (tt); tasting is dominant (T)
Two taster parents (both Tt) can have a non-taster child (tt)
Compounds related to PTC occur in broccoli and Brussels sprouts, which is why some people find them bitter
Suppose a couple are both Ww (widow's peak) and both Tt (PTC tasters). What is the probability their child will have a widow's peak AND be unable to taste PTC?
Treat each character independently
Probability of widow's peak from Ww x Ww = 3/4
Probability of non-taster from Tt x Tt = 1/4
Multiply: 3/4 x 1/4 = 3/16
The disease allele codes for a malfunctioning protein or no protein at all
Heterozygous carriers (Aa) are phenotypically normal because one functional allele (A) produces enough protein
The disorder appears only in homozygous recessive individuals (aa), who inherit a disease allele from each parent
Most affected children are born to two carrier parents (Aa x Aa), giving a 1/4 chance per child
Among unaffected siblings of an affected child, 2/3 are predicted to be carriers
When a disease allele is rare, the chance of two unrelated carriers meeting is low
Close relatives are more likely to carry the same recessive alleles from a shared ancestor, so consanguineous mating increases the risk of homozygous recessive offspring
Defective chloride-channel protein leads to abnormally thick, sticky mucus
Affects the lungs, pancreas, digestive tract, and other organs (pleiotropic)
About 1 in 25 Europeans (4%) are carriers
Frequency: approximately 1 in 2,500 births among people of European descent
Without treatment, can be fatal by age 5; daily antibiotics and mucus-clearing therapies prolong life
Caused by a single amino acid substitution in the haemoglobin protein
In homozygous individuals, haemoglobin aggregates into long fibres under low oxygen, deforming red blood cells into a sickle shape
Sickled cells clog small blood vessels, causing pain, organ damage, and potentially stroke
Affects about 1 in 400 people of African descent; about 1 in 10 African Americans carry the sickle-cell trait
At the organismal level: the normal allele is incompletely dominant (carriers may have mild symptoms under low oxygen)
At the molecular level: the alleles are codominant (heterozygotes produce both normal and sickle haemoglobin)
Evolutionary note: the sickle-cell allele persists because carriers have reduced susceptibility to malaria. The malaria parasite lives in red blood cells, and heterozygous amounts of sickle haemoglobin lower parasite densities.
Only one copy of the disease allele is needed to cause the phenotype
Achondroplasia (a form of dwarfism): heterozygous individuals (Dd) show the dwarf phenotype. Unaffected individuals are homozygous recessive (dd). Occurs in about 1 in 25,000 people.
Lethal dominant alleles are rarer than lethal recessive alleles, because a dominant lethal typically kills before the individual can reproduce and pass it on
Exception: late-onset dominant disorders. Huntington's disease does not show symptoms until ages 35 to 45, by which time the individual may have already had children. The allele is located near the tip of chromosome 4, and a genetic test now exists.
Many diseases have both a genetic component (usually polygenic) and a significant environmental component
Examples: heart disease, diabetes, cancer, schizophrenia, bipolar disorder
Because many genes and environmental variables are involved, these disorders do not follow simple Mendelian patterns
Lifestyle factors (diet, exercise, smoking) can significantly alter risk
Genetic counsellors use pedigree analysis and probability rules to advise prospective parents
Worked example: John and Carol each had a brother who died from the same autosomal recessive disease (allele a). Both sets of parents must be Aa x Aa. John and Carol are unaffected, so each is either AA or Aa. Given the 1:2:1 ratio and the fact they are not aa, each has a 2/3 chance of being a carrier. The probability their first child will be affected = 2/3 x 2/3 x 1/4 = 1/9. If their first child is affected, both parents are confirmed Aa, and the risk for each subsequent child rises to 1/4.
Carrier tests can distinguish AA from Aa individuals for diseases like Tay-Sachs, sickle-cell, and cystic fibrosis
The Genetic Information Nondiscrimination Act (2008) prohibits discrimination in employment or insurance based on genetic test results
Amniocentesis: performed from week 15; extracts amniotic fluid for cell culture and genetic testing
Chorionic villus sampling (CVS): performed from week 10; extracts placental tissue with the fetal genotype. Earlier results than amniocentesis.
PKU screening is routine at birth in many hospitals
Early detection allows a low-phenylalanine diet that prevents intellectual disability
Other disorders are also screened depending on the region
Students often think that if a trait is recessive, it must be rare. Frequency and dominance are independent. A recessive allele can be very common in a population (e.g. the allele for blood type O).
Students sometimes assume that carrier parents will definitely have an affected child. They will not. Each child independently has a 1/4 chance of being affected, a 1/2 chance of being a carrier, and a 1/4 chance of being homozygous normal.
Students frequently think Huntington's disease is recessive because it is rare. It is dominant. Its rarity is because a single copy of the allele is sufficient to cause the disease, and affected individuals often do not reproduce before diagnosis (though late onset complicates this).
Students often confuse amniocentesis with CVS. The key differences: amniocentesis is performed later (week 15) and samples amniotic fluid; CVS is performed earlier (week 10) and samples placental tissue.
⚠️ Be able to look at a pedigree and determine whether a trait is dominant or recessive. The key clue: if two unaffected parents have an affected child, the trait is recessive. If the trait appears in every generation and an affected parent always has at least one affected child, consider dominant.
⚠️ Know the carrier probability shortcut: among the phenotypically normal offspring of two carriers (Aa x Aa), 2/3 are carriers (Aa) and 1/3 are homozygous normal (AA). This 2/3 figure appears in genetic counselling problems constantly.
⚠️ Be ready to calculate multi-step probabilities for genetic counselling scenarios (e.g. the 2/3 x 2/3 x 1/4 = 1/9 pattern when both partners had an affected sibling but are themselves unaffected).
⚠️ Know the distinguishing features of cystic fibrosis, sickle-cell disease, Tay-Sachs, Huntington's disease, achondroplasia, and PKU: inheritance pattern, affected populations, key molecular mechanism, and whether carrier tests or prenatal tests exist.
⚠️ Understand why sickle-cell disease persists in populations where malaria is endemic (heterozygote advantage). This is a favourite exam question bridging genetics and evolution.
True or false: Two phenotypically normal parents cannot have a child with a recessive genetic disorder. (False: both parents can be heterozygous carriers, giving a 1/4 chance per child.)
Fill in the blank: Breeding between close relatives is called ___ mating. (Consanguineous)
True or false: Huntington's disease is caused by a recessive allele. (False: it is caused by a dominant allele with late onset.)
Fill in the blank: Among the unaffected children of two carriers (Aa x Aa), the probability of being a carrier is ___. (2/3)
True or false: Amniocentesis can be performed earlier in pregnancy than chorionic villus sampling. (False: CVS can be performed at week 10; amniocentesis at week 15.)
Q: A couple are both carriers for cystic fibrosis (Cc x Cc). What is the probability that their first child will have the disease? What is the probability that their first two children will both be unaffected?
A: Probability of an affected child (cc) = 1/4. Probability of an unaffected child = 3/4. Probability that the first two children are both unaffected = 3/4 x 3/4 = 9/16.
Q: In a pedigree, two unaffected parents have a son with a genetic disorder. Is the disorder most likely dominant or recessive? What are the parents' most likely genotypes?
A: Recessive. If it were dominant, at least one parent would need to show the trait. Both parents are most likely heterozygous carriers (Aa).
Q: John and Carol each had a sibling who died from an autosomal recessive disorder. Neither John nor Carol is affected. What is the probability that their first child will have the disorder?
A: Each of their parents was Aa x Aa. Since John and Carol are unaffected, they are either AA or Aa. Excluding the aa possibility, each has a 2/3 chance of being Aa. The child would be affected only if both parents are carriers AND the child inherits aa: 2/3 x 2/3 x 1/4 = 4/36 = 1/9.
Q: Why does sickle-cell disease persist at relatively high frequencies in certain populations despite being harmful in homozygotes?
A: Heterozygous carriers (sickle-cell trait) have a selective advantage in regions where malaria is prevalent. The malaria parasite reproduces inside red blood cells, and the presence of some sickle haemoglobin reduces parasite density and malaria symptoms. This heterozygote advantage maintains the allele in the population.
Q: A woman is heterozygous for both widow's peak (Ww) and PTC tasting (Tt). Her partner has the same genotype (Ww, Tt). What is the probability of a child who lacks a widow's peak and cannot taste PTC?
A: Probability of no widow's peak (ww) from Ww x Ww = 1/4. Probability of non-taster (tt) from Tt x Tt = 1/4. These are independent characters, so multiply: 1/4 x 1/4 = 1/16.
Pedigree analysis reappears throughout human genetics and is essential for understanding sex-linked inheritance (Ch. 15). The genetic counselling probability problems here are the same multiplication and addition rule calculations from Section 14.2 (Part 2 of these notes), just applied to real clinical scenarios. Sickle-cell disease bridges genetics and evolutionary biology: it is one of the clearest examples of heterozygote advantage and natural selection acting on a single-gene trait. Multifactorial disorders connect to later discussions of gene-environment interaction and epigenetics.
Human genetics, pedigree analysis, family tree genetics, autosomal recessive, autosomal dominant, carrier genetics, genetic counselling, genetic counselor, cystic fibrosis, CF gene, sickle-cell disease, sickle-cell trait, heterozygote advantage, malaria resistance, Tay-Sachs disease, Huntington's disease, achondroplasia, dwarfism genetics, amniocentesis, chorionic villus sampling, CVS, prenatal testing, newborn screening, phenylketonuria, PKU, consanguinity, inbreeding genetics, multifactorial disease, polygenic disease, genetic testing, GINA Act, genetic nondiscrimination