The Chromosomal Basis of Inheritance

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Concept 15.1: Mendelian Inheritance and the Chromosome Theory

Historical Foundations

The physical basis of Mendelian inheritance was established by correlating the behavior of chromosomes with the inheritance of traits. Early 20th-century experiments provided evidence that genes are located on chromosomes.

Mendel's "hereditary units" were theoretical until parallels were drawn between their behavior and that of chromosomes during meiosis.
Sutton and Boveri (c. 1902) independently developed the chromosome theory of inheritance, proposing that genes are located on chromosomes.

Thomas Hunt Morgan's Experiments

Morgan used Drosophila melanogaster (fruit flies) for genetic studies due to their short generation time, high offspring number, and only four pairs of chromosomes.
He distinguished between wild type (common) and mutant phenotypes (alternative traits).
The first mutant discovered was a white-eyed fly, compared to the wild-type red eyes.

Scientific Inquiry: Correlating Genes and Chromosomes

Morgan crossed white-eyed males with red-eyed females. All F1 offspring had red eyes; F2 showed a 3:1 red to white ratio, but only males had white eyes.
He concluded the white-eye allele was located on the X chromosome, supporting the chromosome theory of inheritance.

Concept 15.2: Sex-Linked Genes and Patterns of Inheritance

The Chromosomal Basis of Sex

Sex is determined by specific combinations of sex chromosomes, which vary among organisms.

Humans and most mammals: XX (female), XY (male).
The SRY gene on the Y chromosome triggers male development.
Short homologous regions at the ends of X and Y allow pairing during meiosis.

Sex-Linked Genes

Sex-linked gene: Located on either sex chromosome.
Y-linked genes: Only 78 genes, mostly related to sex determination.
X-linked genes: About 1,100 genes, many unrelated to sex.

Inheritance of X-Linked Genes

Females (XX) need two copies of a recessive allele to express an X-linked trait (homozygous).
Males (XY) need only one copy (hemizygous), making X-linked recessive disorders more common in males.
Examples: Color blindness, Duchenne muscular dystrophy, hemophilia.

X Inactivation in Female Mammals

One X chromosome in each cell is randomly inactivated during embryonic development, forming a Barr body.
Females heterozygous for X-linked genes are mosaics for those traits.
Inactivation involves DNA and histone modification; the XIST gene is crucial for this process.

Concept 15.3: Linked Genes and Genetic Recombination

Linked Genes

Genes located near each other on the same chromosome tend to be inherited together.

Linked genes: Do not assort independently.
Morgan's experiments with fruit flies showed that certain trait combinations appeared more frequently than expected, indicating linkage.

Genetic Recombination

Genetic recombination: Production of offspring with combinations of traits differing from either parent.
Parental types: Offspring with parental phenotypes.
Recombinant types: Offspring with new trait combinations.
A 50% recombination frequency indicates genes are on different chromosomes (unlinked).

Crossing Over

Linked genes can be separated by crossing over during meiosis, producing recombinant chromosomes.
This process increases genetic variation, which is essential for natural selection.

Mapping Genes: Linkage Maps

Genetic map: Ordered list of gene loci on a chromosome.
Linkage map: Based on recombination frequencies; one map unit = 1% recombination frequency.
Genes far apart on the same chromosome can have recombination frequencies near 50% and behave as if unlinked.
Sturtevant used recombination data to map fruit fly genes, finding four linkage groups corresponding to the four chromosomes in Drosophila.

Concept 15.4: Alterations of Chromosome Number or Structure

Abnormal Chromosome Number

Nondisjunction: Failure of homologous chromosomes or sister chromatids to separate properly during meiosis.
Results in gametes with abnormal chromosome numbers.
Aneuploidy: Abnormal number of a particular chromosome.
Monosomic: One copy of a chromosome.
Trisomic: Three copies of a chromosome.
Polyploidy: More than two complete sets of chromosomes (e.g., triploidy (3n), tetraploidy (4n)); common in plants.

Alterations of Chromosome Structure

Deletion: Loss of a chromosomal fragment.
Duplication: Repetition of a segment.
Inversion: Reversal of a segment within a chromosome.
Translocation: Movement of a segment to a nonhomologous chromosome.

Human Disorders Due to Chromosomal Alterations

Down syndrome (Trisomy 21): Three copies of chromosome 21; frequency increases with maternal age.
Klinefelter syndrome (XXY): Males with an extra X chromosome; sterile, some female characteristics.
XYY males: No syndrome, generally normal.
XXX females: Generally healthy, possible learning disabilities.
Turner syndrome (X0): Females with only one X chromosome; sterile, only viable human monosomy.
Cri du chat syndrome: Deletion on chromosome 5; severe intellectual disability, catlike cry.
Chronic myelogenous leukemia (CML): Caused by chromosomal translocation.

Concept 15.5: Exceptions to Standard Mendelian Inheritance

Genomic Imprinting

Genomic imprinting: Phenotype depends on which parent passed along the allele.
Involves silencing of certain genes via methylation of DNA (—CH3 groups added to cytosine nucleotides).
Most imprinted genes are autosomal and critical for embryonic development.
Example: Only the paternal allele of the mouse Igf2 gene is expressed.

Inheritance of Organelle Genes

Extranuclear (cytoplasmic) genes: Located in mitochondria and chloroplasts, inherited maternally.
First evidence: Inheritance of leaf color in plants.
Defects in mitochondrial genes can cause diseases affecting muscles and nerves (e.g., mitochondrial myopathy, Leber’s hereditary optic neuropathy).
Potential therapy: Transferring chromosomes from an affected mother's egg to a healthy donor egg to prevent mitochondrial disorders.

Summary Table: Types of Chromosomal Alterations

Alteration Type	Description	Example Disorder
Aneuploidy	Abnormal number of a particular chromosome	Down syndrome (Trisomy 21), Turner syndrome (X0)
Polyploidy	More than two complete sets of chromosomes	Common in plants
Deletion	Loss of a chromosomal segment	Cri du chat syndrome
Duplication	Repetition of a segment	Some cancers
Inversion	Reversal of a segment within a chromosome	May cause developmental issues
Translocation	Segment moves to a nonhomologous chromosome	Chronic myelogenous leukemia (CML)

Key Equations and Definitions

Map unit (centimorgan): One map unit = 1% recombination frequency
Recombination frequency formula:

Hemizygous: Having only one allele for a gene (e.g., X-linked genes in males)
Barr body: Inactivated X chromosome in female cells
Genomic imprinting: Differential expression of a gene depending on parental origin

Additional info:

Random fertilization and crossing over during meiosis greatly increase genetic diversity in sexually reproducing organisms.
Linkage maps are not physical maps; they show relative positions based on recombination frequencies, not actual distances in base pairs.