Chromosomal Basis of Inheritance

Chromosome Theory of Inheritance

The chromosome theory of inheritance states that genes are located on chromosomes and that the behavior of chromosomes during meiosis accounts for Mendel's laws of segregation and independent assortment.

Key Principles

• Genes have specific loci (positions) on chromosomes
• Chromosomes undergo segregation during meiosis I → explains Mendel's Law of Segregation
• Chromosomes on different pairs assort independently → explains Mendel's Law of Independent Assortment
• Each chromosome carries hundreds to thousands of genes

Historical Development

The Sutton-Boveri hypothesis proposed that chromosomes are the physical carriers of genes — a revolutionary idea that unified cytology and genetics.

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Linkage Groups

A linkage group is a set of genes located on the same chromosome that tend to be inherited together.

Why Linkage Matters

• Mendel's Law of Independent Assortment applies only to genes on different chromosomes
• Genes on the same chromosome do NOT assort independently — they are linked
• The number of linkage groups equals the haploid chromosome number (n)

Linked vs. Unlinked Genes

• Unlinked genes (on different chromosomes): produce a 1:1:1:1 ratio in test cross offspring
• Completely linked genes: produce only parental types (no recombinants)
• Partially linked genes: produce mostly parental types with some recombinant types

💡 Crossing over during prophase I of meiosis can separate linked genes, producing recombinant chromosomes.

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Morgan's Drosophila Experiments

Thomas Hunt Morgan used the fruit fly Drosophila melanogaster as a model organism because of its advantages:

• Short generation time (~2 weeks)
• Prolific reproduction (hundreds of offspring)
• Only 4 pairs of chromosomes (easy to study)
• Many visible mutations (eye color, wing shape, body color)

The White-Eye Discovery (1910)

Morgan crossed a white-eyed male fly with a red-eyed (wild-type) female:

P cross: ♀ red-eyed × ♂ white-eyed $F_{1}$: All red-eyed (red is dominant)

$F_{1}$ × $F_{1}$ cross:

• $F_{2}$ females: all red-eyed
• $F_{2}$ males: ½ red-eyed, ½ white-eyed

Morgan's Conclusion

The white-eye gene must be on the X chromosome:

• Males have only one X → a single recessive allele is expressed
• Females have two X chromosomes → need two copies of the recessive allele

This was the first gene mapped to a specific chromosome, directly supporting the chromosome theory of inheritance.

🔬 Morgan won the Nobel Prize in Physiology or Medicine in 1933 for his discoveries concerning the role of chromosomes in heredity.

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Sex-Linked Traits

Sex-linked traits are controlled by genes located on the sex chromosomes (X or Y). Because males and females have different combinations of sex chromosomes, these traits show distinctive inheritance patterns.

Sex Determination

In the XX-XY system:

• The X chromosome is large, carrying ~800 genes
• The Y chromosome is small, carrying ~50 genes (mostly involved in male development)
• The SRY gene on the Y chromosome triggers male development

X-Linked Recessive Traits

X-linked recessive traits are the most commonly tested sex-linked pattern on the AP exam.

Key Characteristics

• More common in males than females
• Males need only one copy of the recessive allele (hemizygous: $X^{a}$ Y)
• Females need two copies to express the trait $(X^{a}X^{a})$
• Carrier females $(X^{A} X^{a})$ are phenotypically normal but can pass the allele to sons
• An affected male gets the allele from his mother (never from father)
• An affected father passes the allele to all daughters (who become carriers) but no sons

Classic Examples

Punnett Square: Carrier Female × Normal Male

           $X^{A}$        $X^{a}$
  $X^{A}$    $X^{A}$ $X^{A}$    $X^{A}$ $X^{a}$
          (normal ♀)  (carrier ♀)
  Y      $X^{A}$ Y      $X^{a}$ Y
          (normal ♂)  (affected ♂)

Result: 50% of sons affected, 50% of daughters are carriers

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X-Linked Dominant Traits

X-linked dominant traits are expressed in both heterozygous females and hemizygous males.

Characteristics

• Affected males pass the trait to all daughters and no sons
• Affected heterozygous females pass to 50% of all children regardless of sex
• Often more common in females (they have two X chromosomes, so two chances to inherit)
• May be lethal in males (e.g., Rett syndrome, incontinentia pigmenti)

Examples

• Hypophosphatemic rickets (vitamin D-resistant rickets)
• Rett syndrome (usually lethal in males)

Y-Linked (Holandric) Traits

Genes on the Y chromosome that have no counterpart on the X:

• Passed exclusively from father to son
• All sons of an affected father are affected
• No daughters ever inherit the trait
• Very few Y-linked genes affect phenotype beyond sex determination

Examples

• SRY (sex-determining region Y)
• Hairy ear rims (hypertrichosis pinnae auris — debated)
• Some azoospermia factors (AZF) affecting male fertility

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Linked Genes & Recombination

When genes are on the same chromosome, they tend to be inherited together — this is genetic linkage. However, crossing over during meiosis can shuffle linked alleles, producing recombinant offspring.

Parental vs. Recombinant Types

Consider two linked genes (A and B) on the same chromosome:

Example

If a parent has alleles AB on one chromosome and ab on the homolog:

• Parental gametes: AB, ab
• Recombinant gametes: Ab, aB (from crossing over)

💡 Key rule: If two genes are linked, the recombinant classes will always be less frequent than the parental classes. If they're unlinked, all four classes appear in roughly equal proportions (~25% each).

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Recombination Frequency & Map Distance

Recombination frequency (RF) measures how often crossing over separates two linked genes.

Calculating RF

$RF = \frac{\text{Number of recombinant offspring}}{\text{Total offspring}} \times 100\%$

Map Distance

• 1% recombination frequency = 1 centimorgan (cM) = 1 map unit (m.u.)
• Named after Thomas Hunt Morgan
• Alfred Sturtevant (Morgan's student) created the first genetic map in 1913 using Drosophila

Important Limits

⚠️ RF never exceeds 50% because at most 50% of the meiotic products from a single crossover are recombinant (only 2 of 4 chromatids participate in any single crossover event).

Example Calculation

A test cross produces:

• 412 parental type 1
• 388 parental type 2
• 97 recombinant type 1
• 103 recombinant type 2

$RF = \frac{97 + 103}{412 + 388 + 97 + 103} \times 100\% = \frac{200}{1000} \times 100\% = 20\%$

Map distance = 20 cM (the genes are 20 map units apart)

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Three-Point Test Cross & Gene Mapping

A three-point test cross allows you to determine the order of three linked genes and the distances between them simultaneously.

Steps for a Three-Point Cross

1. Identify the parental classes — the two most frequent phenotype classes
2. Identify the double crossover (DCO) classes — the two least frequent classes
3. Determine gene order — compare DCO classes to parental classes; the allele that "switches" in the DCO reveals the middle gene
4. Calculate map distances:
   • Distance A–B = (single CO between A and B + DCO) / total × 100%
   • Distance B–C = (single CO between B and C + DCO) / total × 100%

Interference & Coefficient of Coincidence

$\text{Coefficient of Coincidence (c.o.c.)} = \frac{\text{Observed DCO}}{\text{Expected DCO}}$

$\text{Expected DCO} = (\text{distance 1}) \times (\text{distance 2}) \times \text{total offspring}$

$\text{Interference (I)} = 1 - \text{c.o.c.}$

• I = 0: No interference (crossovers occur independently)
• I > 0: Positive interference (one crossover inhibits nearby crossovers) — most common
• I < 0: Negative interference (one crossover stimulates nearby crossovers) — rare

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Chromosomal Mutations — Changes in Chromosome Number

Chromosomal mutations involve changes in the number or structure of chromosomes. These large-scale alterations can have dramatic effects on phenotype and are a significant source of genetic disorders.

Nondisjunction

Nondisjunction is the failure of chromosomes (or chromatids) to separate properly during cell division.

When It Occurs

Consequences

After fertilization with a normal gamete:

• Gamete with extra chromosome → trisomy (2n + 1)
• Gamete with missing chromosome → monosomy (2n − 1)

⚠️ Most aneuploid embryos are spontaneously aborted. It is estimated that ~25% of all conceptions involve chromosomal abnormalities.

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Aneuploid Conditions in Humans

Autosomal Aneuploidy

💡 Why chromosome 21? Chromosome 21 is the smallest autosome with the fewest genes (~200), which is why trisomy 21 is the most survivable autosomal trisomy.

Sex Chromosome Aneuploidy

Why Sex Chromosome Aneuploidies Are More Survivable

• X-inactivation (Lyon hypothesis): In any cell with more than one X, extra X chromosomes are inactivated as Barr bodies
• The Y chromosome carries few essential genes
• Therefore, sex chromosome aneuploidies cause less gene dosage imbalance

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Polyploidy

Polyploidy involves having more than two complete sets of chromosomes.

Polyploidy in Nature

• Rare in animals — usually lethal (disrupts sex determination and development)
• Common in plants — many crop species are polyploid:
  • Wheat (Triticum aestivum): hexaploid (6n = 42)
  • Potato (Solanum tuberosum): tetraploid (4n = 48)
  • Banana: triploid (3n) — seedless!
  • Strawberry: octoploid (8n = 56)

Types of Polyploidy

• Autopolyploidy: Extra chromosome sets from the same species (e.g., failure of cell division)
• Allopolyploidy: Chromosome sets from two different species after hybridization followed by chromosome doubling
  • This is a mechanism of instant speciation — the allopolyploid is reproductively isolated from both parent species

🌾 Allopolyploidy has been critically important in the evolution of crop plants and is a major mechanism of speciation in plants.

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Structural Chromosomal Changes

Structural chromosomal abnormalities involve rearrangements of chromosome segments rather than changes in chromosome number. These can arise from errors in DNA repair, recombination, or breakage.

Four Major Types

💡 These changes affect gene dosage, gene regulation, and can disrupt genes at breakpoints.

Deletions

A deletion occurs when a chromosomal segment is lost.

Effects

• Loss of genes → usually detrimental
• Pseudodominance: A recessive allele on the normal homolog is expressed because the dominant allele is deleted
• Large deletions are often lethal

Human Example: Cri-du-chat Syndrome

• Deletion of part of chromosome 5p (short arm)
• Characteristic high-pitched cry (like a cat) in infants
• Intellectual disability, microcephaly, distinctive facial features
• Karyotype notation: 46, XX/XY, del(5p)

Duplications

A duplication occurs when a chromosomal segment is copied, resulting in extra genetic material.

Effects

• Generally less harmful than deletions (extra genes vs. missing genes)
• Can lead to gene redundancy → evolutionary raw material for new gene functions
• May cause problems through gene dosage effects

Evolutionary Importance

• The globin gene family (α-globin, β-globin, myoglobin) evolved through ancient gene duplications
• Duplicated genes can diverge over time through mutation:
  • One copy maintains the original function
  • The other copy can evolve a new function (neofunctionalization)
  • Or both copies may specialize (subfunctionalization)
  • Or the extra copy may accumulate mutations and become a pseudogene

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Inversions

An inversion occurs when a chromosome segment breaks at two points, flips 180°, and reinserts.

Types

• Paracentric inversion: Does NOT include the centromere
• Pericentric inversion: INCLUDES the centromere

Effects

• The organism may be phenotypically normal (all genes are present, just rearranged)
• Problems arise during meiosis: crossing over within an inversion loop produces abnormal gametes
  • Paracentric: produces acentric fragments and dicentric chromosomes
  • Pericentric: produces unbalanced gametes (deletions/duplications)
• Inversions can act as crossover suppressors, keeping linked allele combinations intact

Translocations

A translocation is the transfer of a chromosomal segment to a non-homologous chromosome.

Types

• Reciprocal translocation: Segments are exchanged between two non-homologous chromosomes
• Robertsonian translocation: Two acrocentric chromosomes fuse at their centromeres, reducing chromosome number

Human Example: Philadelphia Chromosome

• Reciprocal translocation t(9;22)
• The ABL proto-oncogene (chromosome 9) fuses with the BCR gene (chromosome 22)
• Creates the BCR-ABL fusion gene → constitutively active tyrosine kinase
• Causes chronic myelogenous leukemia (CML)
• Targeted by the drug imatinib (Gleevec)

Robertsonian Translocation & Down Syndrome

• ~4% of Down syndrome cases result from a Robertsonian translocation involving chromosome 21
• Most commonly t(14;21): chromosome 21 fuses to chromosome 14
• The individual has 45 chromosomes but effectively three copies of chromosome 21 genes
• Unlike trisomy 21, translocation Down syndrome is not related to maternal age and may recur in families

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Genomic Imprinting & Extranuclear Inheritance

Not all inheritance follows standard Mendelian patterns. Genomic imprinting and extranuclear inheritance demonstrate that the source of an allele (which parent) and the location of genes (nucleus vs. organelles) can both influence phenotype.

Genomic Imprinting

Genomic imprinting is an epigenetic phenomenon where certain genes are expressed differently depending on whether they were inherited from the mother or the father.

How It Works

• Specific genes are silenced (imprinted) by DNA methylation during gamete formation
• The imprint is parent-of-origin specific: one parental allele is always silenced
• Result: only one allele is expressed (monoallelic expression)
• Imprints are erased and reset each generation during gametogenesis

Key Points

• ~100–200 imprinted genes have been identified in mammals
• Imprinting does NOT change the DNA sequence — it's epigenetic (methylation, histone modification)
• Both the maternal AND paternal copies are needed for normal development

Imprinting Disorders

Prader-Willi Syndrome vs. Angelman Syndrome

These two syndromes beautifully illustrate genomic imprinting — both involve the same region of chromosome 15 (15q11-13) but result from losing the contribution of different parents.

💡 UPD (Uniparental Disomy): Inheriting both copies of a chromosome from ONE parent. If both copies come from the "wrong" parent (the one whose genes are normally imprinted), disease results.

Igf2 Gene (Insulin-like Growth Factor 2)

• Classic example of an imprinted gene
• Maternally imprinted (maternal copy is silenced)
• Only the paternal copy is expressed
• Promotes fetal growth — "parental conflict" hypothesis: father's genes favor larger offspring, mother's genes limit offspring size

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Extranuclear (Cytoplasmic) Inheritance

Some genes are located outside the nucleus — in mitochondria and chloroplasts. These organelles have their own circular DNA and show a unique pattern of inheritance.

Mitochondrial DNA (mtDNA)

• Human mtDNA: 16,569 bp, circular, encodes 37 genes
• Encodes: 13 proteins (electron transport chain), 22 tRNAs, 2 rRNAs
• Maternal inheritance: mitochondria in the egg are passed to all offspring; sperm contribute essentially no mitochondria
• No recombination: mtDNA is clonally inherited
• High mutation rate: ~10× higher than nuclear DNA (no histones, limited repair)
• Heteroplasmy: A cell can contain a mix of normal and mutant mitochondria

Mitochondrial Diseases

Inheritance Pattern

• Affected mother → all children may be affected (maternal inheritance)
• Affected father → no children affected
• Severity can vary due to heteroplasmy — the proportion of mutant vs. normal mitochondria

Maternal Effect Genes

Maternal effect (not the same as maternal inheritance): Gene products deposited in the egg by the mother determine early embryonic phenotype.

Example: Snail Shell Coiling in Lymnaea

• The mother's genotype (not the offspring's) determines the direction of shell coiling
• Dextral (right-coiling, D) is dominant over sinistral (left-coiling, d)
• A dd mother will produce sinistral offspring even if the offspring are Dd
• The effect is delayed one generation because maternal mRNA in the egg directs early development

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Concept Check 🎯

AP Exam Practice — Chromosomal Inheritance Problems

This section contains multi-step genetics problems similar to those on the AP Biology exam. Work through each problem carefully, applying concepts from the entire unit.

Problem-Solving Strategy

1. Identify the inheritance pattern (autosomal vs. sex-linked, dominant vs. recessive, linked vs. unlinked)
2. Assign genotypes to all known individuals
3. Set up appropriate crosses (Punnett squares, branch diagrams)
4. Calculate expected ratios and compare to observed data
5. Check your work — do the ratios make biological sense?

Practice Problem Set 1: Sex-Linked Crosses 🎯

Gene Mapping Practice

Problem: Two-Point Test Cross

A test cross involving two linked genes produces the following offspring:

Step 1: Identify parental and recombinant classes

• Parental: AB (354) and ab (346) → total = 700
• Recombinant: Ab (52) and aB (48) → total = 100

Step 2: Calculate recombination frequency

$RF = \frac{100}{800} \times 100\% = 12.5\%$

Step 3: Map distance = 12.5 cM

The genes are 12.5 centimorgans apart on the same chromosome.

Practice Problem Set 2: Gene Mapping 🎯

Practice Problem 3: Karyotype Analysis 🔍

Practice Problem Set 3: Multi-Step Problems 🎯