L08 Genetics Introduction to Inheritance and Risk Assessment Tut

Overview

This lecture builds from the molecular basis of gene expression and dosage up to the inheritance patterns of single-gene (monogenic) disorders, showing how to read a pedigree for each pattern (autosomal dominant, autosomal recessive, X-linked, Y-linked, mitochondrial), the complications of incomplete penetrance, anticipation, de novo mutation and locus/allelic heterogeneity, and finally how to calculate offspring and population disease risk from allele frequencies using the Hardy-Weinberg equation.

Gene expression, dosage and terminology

• Normal gene expression means a functional gene product is produced in the right amount (gene dosage), at the right time, and in the right cell type. Abnormal expression is any deviation: too little or too much product, no product, decreased or abnormal function, or expression in the wrong cell/time.
• The genotype is the set of genes an organism carries responsible for a trait; the phenotype is the observable physical expression of that trait, shaped by genotype, environment and lifestyle.
• Alleles are different sequence forms of the same gene. Humans are diploid, so autosomal genes normally have two copies (gene dosage): identical copies are homozygous, different alleles are heterozygous. The paired copies (one maternal, one paternal) sit at the same locus.
• Gene dosage is the amount of functional gene product the cell can express; it depends on regulation of expression and on genetic abnormalities such as copy number changes of whole/partial chromosomes or single genes.
• A single gene (monogenic/Mendelian) disorder is caused by an abnormality in one specific gene; the pathway runs gene → transcription/translation → protein → phenotype. Examples: cystic fibrosis, sickle cell disease, Fragile X, Duchenne muscular dystrophy, Huntington disease, Tay-Sachs disease, polycystic kidney disease.

Dominant and recessive alleles

• A dominant allele shows a phenotypic effect even with only one copy. When the dominant allele is the mutant one, 50% of normal gene product is not enough for a normal phenotype, so the heterozygote is affected; there is a phenotypic difference between one (50%) and two (100%) functional alleles. If the mutant allele is partially functional (contributing 1-49%), overall heterozygote dosage is 51-99%, and higher residual expression usually means a milder phenotype.
• A recessive allele shows no phenotypic effect with only one copy. When the recessive allele is the mutant one, 50% of normal gene product is sufficient for a normal phenotype, so only the homozygous mutant genotype is affected; heterozygotes (50% dosage) are phenotypically normal, the same as homozygous normal (100%) individuals. If both mutant copies in a homozygote are partially functional, overall dosage is 2-98%, and again higher residual expression tends to give a milder phenotype.
• For autosomal alleles: dominant+dominant and dominant+recessive genotypes both give a dominant phenotype; only recessive+recessive gives a recessive phenotype.

Penetrance and expressivity

• Penetrance is the proportion of individuals with a given genotype who also show the associated phenotype (e.g. 70% penetrance means 70% of those with the disease genotype display the disease).
• Expressivity is the degree to which the phenotype is displayed between individuals who do show it: high expressivity tends to give a severe phenotype, low expressivity a mild one.
• These are independent axes: a condition can show variable penetrance alone, variable expressivity alone, or both together, which complicates pedigree interpretation.

Autosomal dominant inheritance

• Complete dominance: the dominant allele’s effect in a heterozygote completely masks the recessive allele. An affected (heterozygous) parent of either sex gives 50% affected offspring, regardless of offspring sex.
• Pedigree signature: affected individuals normally appear in every generation, and both sexes are affected equally regardless of the affected parent’s sex. Examples: DiGeorge syndrome, neurofibromatosis type 1, Huntington disease, myotonic dystrophy, familial hypercholesterolaemia, retinitis pigmentosa.
• Incomplete penetrance complicates this pattern: some individuals who must carry the dominant disease genotype (because an affected parent and an affected child bracket them) show no phenotype themselves, so a generation can appear “skipped” even though transmission is dominant. Familial breast cancer from a BRCA1 mutation is given as an example, with about 80% penetrance.

Autosomal recessive inheritance

• Two heterozygous (unaffected carrier) parents: 25% affected offspring, 50% unaffected carrier offspring, 25% unaffected offspring with the normal genotype, irrespective of sex.
• One heterozygous carrier parent and one homozygous-normal parent: 50% unaffected carrier offspring, 50% unaffected normal-genotype offspring.
• Examples: sickle cell anaemia, cystic fibrosis, Tay-Sachs disease, retinitis pigmentosa.
• Because carriers are phenotypically normal, the disease allele can pass silently through several generations before two carriers have children together, so the phenotype appears and disappears suddenly in a family (skips generations) even though transmission follows standard Mendelian rules throughout. Autosomal recessive disorders are more common when close relatives have children together.

X-linked and Y-linked inheritance

• X-linked dominant: an affected mother gives 50% affected sons and 50% affected daughters. Examples (mostly rare): Rett syndrome, Fragile X syndrome.
• X-linked recessive: a carrier mother gives 50% of sons affected and, among daughters, 50% carriers and 50% homozygous normal (no affected daughters). An affected father gives no affected sons and 100% unaffected carrier daughters. Examples: red-green colour blindness, haemophilia A and B, Duchenne muscular dystrophy, retinitis pigmentosa.
• Y-linked: 100% of sons affected, no daughters affected, since the Y chromosome passes only father to son. Examples: Y-linked infertility, testis development disorders, and (not a disease) baldness.

Mitochondrial inheritance

• Mitochondrial DNA (about 1% of total cellular DNA) is inherited maternally: an affected mother transmits the condition to all her children (sons and daughters), with severity varying between children depending on the proportion of affected mitochondria they inherit (heteroplasmy); an affected father transmits it to none of his children.
• Examples: some forms of deafness, Leigh syndrome, Leber’s hereditary optic neuropathy, retinitis pigmentosa (as part of NARP syndrome).

Anticipation and dynamic mutations

• Anticipation is when a dominant condition’s phenotype becomes more severe and/or develops earlier in each successive generation. It is associated with trinucleotide repeat expansions that grow larger with each generation (e.g. CAG repeat expansion in the HTT gene adds extra glutamine residues to the protein). Examples: Huntington disease, Fragile X syndrome, myotonic dystrophy.
• Worked example (myotonic dystrophy): a grandmother diagnosed at 55y with 120 repeats (cataracts); her children diagnosed at 48-50y with 500-700 repeats (grip myotonia, facial weakness, cardiac problems); a grandchild diagnosed at birth with 1200 repeats (facial weakness, severe neonatal hypotonia) - later generations affected earlier and more severely as repeat number rises.

De novo mutations

• When a genetic disorder appears with no apparent family history and only a single affected individual, it is most likely a de novo (new) mutation, though mistaken paternity or very low penetrance of an inherited allele are other possible explanations; on a pedigree alone, a de novo case can look identical to certain inherited cases.
• The consequences and severity of a de novo mutation depend on when and where in development it arises: germline (in either parent) versus somatic tissue, and which sector of tissue carries the mutant cells, determines whether and how it is transmitted to or expressed in offspring.

Locus and allelic heterogeneity

• Allelic heterogeneity is when multiple different mutations (alleles) at the same locus all produce the same phenotype, which can still vary in severity. Example: over 1400 different mutations identified in the CFTR gene all cause cystic fibrosis.
• Locus heterogeneity is when mutations at multiple different, unrelated loci each independently cause the same disease phenotype. Example: at least 45 autosomal recessive retinitis pigmentosa genes exist (plus others following other inheritance patterns). Most disorders showing locus heterogeneity also show allelic heterogeneity.
• Worked example: two deaf parents, each deaf due to a homozygous mutation at a different locus (locus heterogeneity), can have children who inherit only one non-functional copy per locus (hearing, carriers) or two non-functional copies at the same locus (deaf), depending on which parental alleles combine.

Because deafness in that couple arises from different genes in each parent, some of their children can be hearing even though both parents are deaf, since a child needs two non-functional copies at the same locus to be affected.

Calculating disease risk from allele frequencies

• For a gene with two alleles, p is the frequency of the normal (or dominant) allele and q the frequency of the abnormal (or recessive) allele, where $p+q=1$.
• Hardy-Weinberg equilibrium: $p^2+2pq+q^2=1$, where $p^2$ is the frequency of the homozygous dominant genotype, $q^2$ the frequency of the homozygous recessive genotype, and $2pq$ the frequency of the heterozygous (carrier) genotype.
• To calculate an offspring’s risk of being affected or a carrier, the parents’ genotype probabilities must be known. Worked principle: in an autosomal recessive disorder, if one individual has the clear affected (aa) phenotype and both parents are known Aa carriers, then any of their unaffected offspring has a 2/3 (67%) chance of being a carrier (the aa possibility is excluded because the offspring is stated to be unaffected, leaving AA : Aa : Aa in a 1:2 ratio among the remaining possibilities).

The lecture's worked risk-calculation example (a pedigree with an affected individual in generation II on each side of the family and an unknown "?" individual in generation III) was completed live in class using blank Punnett squares and the Hardy-Weinberg equation from the preceding section. The transcript source (a printed slide deck) shows the pedigree and blank grids but no filled-in values: the specific q, p, 2pq and final "overall risk" figures, including for the final question (population carrier risk given an abnormal allele frequency of 1/20), are not recorded on the slides and are not given here.

Self-test

1. Define genotype and phenotype, and explain what determines the phenotype besides the genotype.
2. Distinguish homozygous from heterozygous, and define gene dosage.
3. List the conditions required for “normal” gene expression, and list the ways gene expression can become abnormal.
4. Distinguish a dominant allele from a recessive allele in terms of the phenotypic effect of a single copy and the gene dosage produced by a heterozygote.
5. Predict the phenotype for each of the three possible autosomal genotype combinations of a dominant and a recessive allele.
6. Define penetrance and expressivity, and explain how they differ from one another.
7. Describe the pedigree features that indicate autosomal dominant inheritance, and give two example diseases.
8. Explain, using the BRCA1 example, how incomplete penetrance can make an obligate carrier of a dominant allele appear unaffected in a pedigree.
9. State the offspring probabilities for autosomal recessive inheritance when both parents are heterozygous carriers, and when one parent is a carrier and the other is homozygous normal.
10. Explain why an autosomal recessive disease can appear to skip generations in a family, and what factor increases the frequency of these disorders.
11. Describe the pattern of affected sons and daughters for X-linked dominant inheritance from an affected mother, and for X-linked recessive inheritance from an affected father.
12. Describe the inheritance pattern of a Y-linked allele.
13. Describe the pattern of transmission of a mitochondrial disease from an affected mother versus an affected father, and explain why affected siblings can differ in severity.
14. Define anticipation and describe the molecular mechanism that produces it, using the myotonic dystrophy pedigree as an example.
15. A child is affected by a genetic disorder with no family history of it. Describe the most likely explanation and two alternative explanations, and explain what determines the severity of the most likely explanation.
16. Distinguish allelic heterogeneity from locus heterogeneity, giving one example of each from the lecture.
17. In the two-deaf-parents worked example, explain how two deaf parents can have a hearing child.
18. State the Hardy-Weinberg equation and what each term (p, q, p², 2pq, q²) represents.
19. In an autosomal recessive disorder, if an individual has the affected (aa) phenotype and both parents are confirmed Aa carriers, what is the probability that an unaffected sibling is a carrier, and why?
20. Integrative: a newborn is affected by a severe autosomal recessive condition that neither parent has ever shown. Using the concepts of gene dosage, penetrance and carrier frequency from this lecture, explain how both parents can be genetically unaffected yet have an affected child.

Answers

Reveal answers

1. The genotype is the set of genes (and their specific alleles) an organism carries that underlie a trait; the phenotype is the observable physical expression of that trait. Besides genotype, phenotype is also shaped by environmental factors and lifestyle choices.
2. Homozygous means the two allele copies at a locus are identical; heterozygous means the two copies are different alleles. Gene dosage is the number of functional gene copies present (and, by extension, the amount of functional gene product produced).
3. Normal gene expression requires a functional gene product produced in the correct amount (gene dosage), at the right time, and in the right cell type. Abnormal expression includes too little or too much product, no product, decreased or abnormal function of the product, or expression in the wrong cell type or at the wrong time.
4. A dominant allele produces a phenotypic effect even with a single copy, so a heterozygote for a dominant mutant allele is affected despite 50% gene dosage. A recessive allele produces no phenotypic effect with a single copy, so a heterozygote (also 50% dosage) remains phenotypically normal; only a homozygous recessive mutant genotype is affected.
5. Dominant + dominant gives a dominant phenotype; dominant + recessive gives a dominant phenotype; recessive + recessive gives a recessive phenotype.
6. Penetrance is the proportion of individuals with a given genotype who show the associated phenotype at all (e.g. 70% penetrance means 70% of that genotype display the disease). Expressivity is the degree of severity of the phenotype among those who do show it. Penetrance is therefore about whether the phenotype appears; expressivity is about how severe it is once it does.
7. Affected individuals normally appear in every generation, and both sexes are affected equally regardless of which parent is affected. Examples include DiGeorge syndrome, neurofibromatosis type 1, Huntington disease, myotonic dystrophy, familial hypercholesterolaemia, and retinitis pigmentosa (any two).
8. BRCA1 mutations show about 80% penetrance, so an individual who has inherited the dominant disease allele (confirmed by an affected parent on one side and an affected child on the other) can nonetheless show no phenotype themselves, making that generation appear unaffected in the pedigree despite carrying and transmitting the allele.
9. Two heterozygous carrier parents: 25% affected, 50% unaffected carrier, 25% unaffected with the normal genotype (irrespective of sex). One heterozygous carrier and one homozygous normal parent: 50% unaffected carrier, 50% unaffected normal-genotype offspring (no affected offspring).
10. Carriers are phenotypically normal, so the recessive disease allele can be transmitted silently through several generations before two carriers happen to have children together and produce an affected homozygote, making the disease appear and disappear suddenly rather than in every generation. Close relatives having children together increases the frequency of these disorders (shared recessive alleles are more likely to meet).
11. X-linked dominant from an affected mother: 50% of sons affected and 50% of daughters affected. X-linked recessive from an affected father: no affected sons (fathers cannot pass the affected X to sons), and 100% of daughters become unaffected carriers.
12. A Y-linked allele passes only from father to son: 100% of sons are affected, and no daughters are affected, since daughters do not inherit a Y chromosome.
13. An affected mother transmits mitochondrial disease to all of her children (sons and daughters), with severity varying between them depending on the proportion of affected mitochondria (heteroplasmy) each inherits; an affected father transmits it to none of his children, since mitochondria are maternally inherited.
14. Anticipation is when a dominant condition becomes more severe and/or develops earlier in each successive generation. It is caused by a trinucleotide repeat sequence (e.g. CAG in the HTT gene) that expands with each generation, adding more residues (e.g. glutamine) to the protein product; in the myotonic dystrophy example, repeat number rose from 120 (grandmother, diagnosed at 55y) to 500-700 (parents, 48-50y) to 1200 (grandchild, diagnosed at birth), with correspondingly earlier and more severe disease.
15. The most likely explanation is a de novo (new) mutation. Alternative explanations given are mistaken paternity or very low penetrance of an inherited allele. For a de novo mutation, severity depends on when and where in development it arose: germline (in either parent) versus somatic tissue, and which tissue sector carries the mutant cells.
16. Allelic heterogeneity is when different mutations at the same locus all cause the same phenotype (e.g. over 1400 different CFTR mutations all cause cystic fibrosis). Locus heterogeneity is when mutations at different, unrelated loci each independently cause the same phenotype (e.g. at least 45 different autosomal recessive retinitis pigmentosa genes).
17. Because their deafness arises from mutations at two different loci (one parent’s deafness from one gene, the other parent’s from a different gene), a child only becomes deaf if they inherit two non-functional copies at the same locus; a child can instead inherit only one non-functional copy at each locus from each parent, leaving them hearing (a carrier at both loci).
18. $p^2+2pq+q^2=1$, where p is the frequency of the normal/dominant allele and q the frequency of the abnormal/recessive allele (with $p+q=1$); $p^2$ is the frequency of the homozygous dominant genotype, $q^2$ the frequency of the homozygous recessive genotype, and $2pq$ the frequency of the heterozygous genotype.
19. 2/3 (67%). Since the sibling is stated to be unaffected, the aa (homozygous recessive) possibility is excluded, leaving AA : Aa : Aa among the remaining three equally likely outcomes of an Aa x Aa cross, so 2 of the 3 remaining possibilities are carriers.
20. Both parents can be heterozygous (Aa) carriers of the recessive allele: at 50% gene dosage they produce enough normal gene product for a normal phenotype (no disease), so neither parent shows any sign of the condition. If both happen to pass their mutant allele to the child, the child is homozygous recessive (aa), with too little functional gene product, producing the disease phenotype, even though the population frequency of carriers (2pq) can make such a pairing more likely than the disease’s rarity might suggest.