The Chromosomal Basis of Inheritance (Campbell Biology, 10th Edition)

Locating Genes Along Chromosomes and the Chromosome Theory

• Mendel’s "hereditary factors" were initially purely abstract concepts with no known physical location.

• Today, biology recognizes that these factors—genes—are located on chromosomes.

• The specific location (locus) of a particular gene can be visualized by tagging isolated chromosomes with fluorescent dyes that highlight the gene.

• The chromosomal basis of inheritance began to take shape as cytologists and biologists noted parallels between the behavior of Mendel’s factors and the behavior of chromosomes:

  • In $1875$, cytologists used improved microscopy techniques to work out the process of mitosis.

  • Around $1902$, Sutton, Boveri, and others identified parallels between Mendelian factors and chromosomal behavior.

  • Mendel's Law of Segregation: The two alleles for each gene separate during gamete formation, which corresponds to the separation of homologous chromosomes during meiosis.

  • Mendel's Law of Independent Assortment: Alleles of genes on nonhomologous chromosomes assort independently, which corresponds to the independent alignment and separation of nonhomologous chromosome pairs during metaphase I and anaphase I.

• In a cross between yellow-round seeds ($YYRR$) and green-wrinkled seeds ($yyrr$):

  • The $F_{1}$ generation consists of all yellow-round seeds ($YyRr$).

  • The $F_{2}$ generation results in a phenotypic ratio of $9 : 3 : 3 : 1$.

Thomas Hunt Morgan and Fruit Fly Genetics

• Thomas Hunt Morgan provided the first solid evidence in the early $20^{\text{th}}$ century that associated a specific gene with a specific chromosome.

• Experimental Organism: Drosophila melanogaster (the common fruit fly).

  • Advantages for genetic study:

    • They produce many offspring per mating.

    • A new generation can be bred every two weeks.

    • They have only four pairs of chromosomes: three pairs of autosomes and one pair of sex chromosomes.

• Terminology for phenotypes:

  • Wild Type: Normal phenotypes observed frequently in nature (e.g., red eyes in fruit flies).

  • Mutant Phenotypes: Alternative traits that deviate from the wild type (e.g., white eyes in fruit flies).

• Morgan’s Red-Eye vs. White-Eye Experiment:

  • Morgan mated white-eyed males (mutant) with red-eyed females (wild type).

  • The $F_{1}$ generation all had red eyes, indicating red was dominant.

  • The $F_{2}$ generation exhibited a $3 : 1$ ratio of red eyes to white eyes.

  • However, only males had white eyes; all females had red eyes.

  • Conclusion: The white-eyed mutant allele must be located on the $X$ chromosome. This confirmed the chromosome theory of inheritance and showed that inheritance patterns can be sex-linked.

The Chromosomal Basis of Sex

• In humans and other mammals, there are two varieties of sex chromosomes: the larger $X$ and the smaller $Y$.

• Sex Determination Systems:

  • The $X-Y$ System: Typical in mammals. Females are $XX$ and males are $XY$. Only the ends of the $Y$ chromosome are homologous with the $X$ chromosome, allowing them to pair during meiosis.

  • The $SRY$ Gene: Located on the $Y$ chromosome (Sex-determining Region on the $Y$), it is responsible for the development of testes in the embryo.

  • The $X-0$ System: Found in some insects (like grasshoppers). Females are $XX$ and males are simply $X$ ($X0$).

  • The $Z-W$ System: Found in birds and some fish. Females are $ZW$ and males are $ZZ$.

  • The Haplo-Diploid System: Found in bees and ants. There are no sex chromosomes; females develop from fertilized eggs (diploid, $32$) and males from unfertilized eggs (haploid, $16$).

• Sex-Linked Genes:

  • $Y$-linked genes: Located on the $Y$ chromosome (very few in number, mostly related to sex determination).

  • $X$-linked genes: Located on the $X$ chromosome (many genes for traits unrelated to sex).

Inheritance of X-Linked Genes and X Inactivation

• Patterns of Inheritance:

  • For a recessive $X$-linked trait to be expressed:

    • A female needs two copies of the allele (homozygous).

    • A male needs only one copy of the allele (hemizygous).

  • Consequently, $X$-linked recessive disorders are much more common in males than in females.

• Human $X$-linked Disorders:

  • Color blindness (mostly $X$-linked).

  • Duchenne muscular dystrophy.

  • Hemophilia.

• $X$ Inactivation in Female Mammals:

  • One of the two $X$ chromosomes in every cell is randomly inactivated during embryonic development.

  • The inactive $X$ condenses into a structure called a Barr body.

  • If a female is heterozygous for a gene on the $X$ chromosome, she will be a mosaic for that character (e.g., tortoiseshell coloration in cats).

Linkage, Recombination, and Mapping

• Linked Genes: Genes located on the same chromosome that tend to be inherited together because they are physically close.

• Genetic Recombination: The production of offspring with combinations of traits differing from those found in either parent.

  • Parental Types: Offspring with a phenotype matching one of the parental phenotypes.

  • Recombinant Types (Recombinants): Offspring with new combinations of traits.

  • For genes on different chromosomes, the recombination frequency is $50\%$.

• Crossing Over: Morgan proposed that linkage is incomplete because some recombinant phenotypes are observed. This is due to crossing over between homologous chromosomes during meiosis.

• Linkage Mapping:

  • Alfred Sturtevant, a student of Morgan, created the first genetic map (an ordered list of genetic loci).

  • Sturtevant’s Prediction: The farther apart two genes are, the higher the probability that a crossover will occur between them, and thus the higher the recombination frequency.

  • Linkage Map: A genetic map based on recombination frequencies.

  • Map Units: Distances between genes are expressed as map units (or centimorgans); one map unit represents a $1\%$ recombination frequency.

  • Genes that are physically linked but far apart on a chromosome can have a recombination frequency near $50\%$, behaving as if they were genetically unlinked.

• Recombination Frequency Calculation in Morgan's Testcross:

  • $\frac{391 \text{ recombinants}}{2,300 \text{ total offspring}} \times 100 = 17\%$

Alterations of Chromosome Number and Structure

• Nondisjunction: Pairs of homologous chromosomes (in Meiosis I) or sister chromatids (in Meiosis II) do not separate normally.

  • Result: One gamete receives two of the same chromosome, while another receives none.

• Aneuploidy: Fertilization involving a gamete in which nondisjunction occurred, leading to an abnormal number of a particular chromosome.

  • Monosomic Zygote: Has only one copy of a particular chromosome.

  • Trisomic Zygote: Has three copies of a particular chromosome.

• Polyploidy: A condition where an organism has more than two complete sets of chromosomes (Triploidy $= 3n$; Tetraploidy $= 4n$). Common in plants, but rare in animals.

• Structural Alterations:

  • Deletion: Removes a chromosomal segment.

  • Duplication: Repeats a segment.

  • Inversion: Reverses the orientation of a segment within the chromosome.

  • Translocation: Moves a segment from one chromosome to a nonhomologous chromosome.

Human Disorders Due to Chromosomal Alterations

• Down Syndrome ($Trisomy \, 21$):

  • Results from three copies of chromosome $21$.

  • Affects approximately $1$ out of every $700$ children born in the US.

  • Frequency increases with maternal age.

• Aneuploidy of Sex Chromosomes:

  • Klinefelter Syndrome: $XXY$ individuals (males).

  • Turner Syndrome ($Monosomy \, X$): $X0$ females (sterile); the only viable monosomy in humans.

  • $XXX$ females: Healthy, no unusual physical features.

• Structural Alteration Disorders:

  • Cri du chat ("cry of the cat"): Results from a specific deletion in chromosome $5$. Characterized by severe intellectual disability and a catlike cry; usually fatal in early childhood.

  • Chronic Myelogenous Leukemia (CML): Caused by a translocation between chromosomes $9$ and $22$, creating the "Philadelphia chromosome."

Exceptions to Standard Mendelian Inheritance

• Genomic Imprinting:

  • The phenotype depends on which parent passed along the allele.

  • Involves the silencing of certain genes, usually via methylation (addition of $-CH_{3}$) of cysteine nucleotides.

  • Example: The $Igf2$ mouse allele. A mutant allele is only expressed if inherited from the father; if inherited from the mother, it is silenced.

• Inheritance of Organelle Genes:

  • Extranuclear genes (cytoplasmic genes) are located in mitochondria, chloroplasts, and other plastids.

  • These organelles carry small circular DNA molecules.

  • Generally inherited maternally because the zygote’s cytoplasm originates from the egg.

  • Disorders: Mitochondrial myopathy and Leber’s hereditary optic neuropathy are caused by defects in mitochondrial genes that impair ATP production.