Unit 4: Patterns of inheritance, sex-linked genetics and genetic mutations - Subjective Questions

Multiple alleles occur when a single gene has more than two alternative forms, or alleles, in a population. However, an individual diploid organism can possess only two alleles of that gene at a time.

• Multiple alleles are produced by repeated mutation of a particular gene locus.
• They occupy the same position, or locus, on homologous chromosomes.
• They may show dominance, recessiveness, or codominance relationships.
• The total number of possible genotypes depends on the number of alleles.

For a gene with alleles, the number of possible diploid genotypes is:

A classic example is the human ABO blood group system, which has three alleles: , , and . The alleles and are codominant, while is recessive to both.

Pleiotropism is the phenomenon in which a single gene influences two or more apparently unrelated phenotypic traits.

• One gene may affect several biochemical or developmental pathways.
• The effects may occur in different tissues or at different stages of development.
• An example is the sickle-cell allele, which affects red blood-cell shape, hemoglobin structure, resistance to malaria, and disease symptoms.

Pseudoalleles are closely linked genes that produce similar or related phenotypic effects and may sometimes show apparent allelic behavior.

• They are located at different but closely adjacent loci.
• Recombination can occur between them, showing that they are not true alleles.
• Pseudoalleles were demonstrated in some Drosophila eye-color loci.

Thus, pleiotropism concerns the effects of one gene on several traits, whereas pseudoalleles concern different, closely linked genes with related effects.

The ABO blood group system is controlled by three alleles: , , and .

• produces the A antigen on red blood cells.
• produces the B antigen.
• produces neither A nor B antigen.
• and are codominant.
• Both and are completely dominant over .

Important parental combinations include:

• A A: children may be A or O, depending on parental genotypes.
• B B: children may be B or O.
• A B: children may be A, B, AB, or O if both parents are heterozygous.
• AB O: children can be A or B, but not AB or O.
• O O: all children are O.

The ABO system is important in blood transfusion and parentage studies.

The Rh blood group system is mainly determined by the presence or absence of the D antigen on red blood cells.

• Individuals with the D antigen are Rh-positive.
• Individuals lacking the D antigen are Rh-negative.
• In a simple genetic model, allele is dominant over allele .
• Rh-positive genotypes are or .
• The Rh-negative genotype is .

When an Rh-negative mother carries an Rh-positive fetus, fetal red blood cells may enter the maternal circulation, especially during delivery. The mother can then produce anti-D antibodies. In a later Rh-positive pregnancy, these antibodies may cross the placenta and destroy fetal red blood cells.

This condition is called hemolytic disease of the newborn or erythroblastosis fetalis. It can be prevented by administering anti-D immunoglobulin to the Rh-negative mother after possible exposure to Rh-positive blood.

In humans, sex is determined by the XX-XY mechanism.

• Females have 46 chromosomes, including two X chromosomes: .
• Males have 44 autosomes and one X and one Y chromosome: .
• All ova carry an X chromosome.
• Half of the sperm carry X and half carry Y.
• Fertilization by an X-bearing sperm produces an XX female, while fertilization by a Y-bearing sperm produces an XY male.

Other sex-determination systems include:

• XO system: Females are XX and males are XO. Males produce X-bearing and O-bearing sperm, as in some insects.
• ZW system: Males are ZZ and females are ZW. The female is the heterogametic sex, as in birds and butterflies.
• Haplodiploid system: Females develop from fertilized diploid eggs, while males develop from unfertilized haploid eggs, as in bees and ants.

Thus, the heterogametic sex differs among systems.

Sex-linked inheritance refers to the transmission of genes located on the sex chromosomes. X-linked traits are controlled by genes on the X chromosome, while Y-linked traits are controlled by genes on the Y chromosome.

For an X-linked recessive trait, let represent the normal allele and represent the recessive disease allele.

• Affected male: .
• Normal male: .
• Carrier female: .
• Affected female: .

A carrier female crossed with a normal male gives:

Possible offspring are:

• : normal daughter.
• : carrier daughter.
• : normal son.
• : affected son.

The trait is more common in males because males have only one X chromosome. There is no father-to-son transmission of an X-linked trait because fathers transmit their Y chromosome to sons.

In X-linked dominant inheritance, a single dominant allele on the X chromosome produces the trait. Let be the dominant disease allele and the normal allele.

A heterozygous affected female crossed with a normal male is represented as:

The expected offspring are:

• : affected daughter.
• : normal daughter.
• : affected son.
• : normal son.

Important differences are:

• In X-linked dominant inheritance, affected fathers transmit the trait to all daughters but no sons.
• In X-linked recessive inheritance, affected fathers do not transmit the trait directly to sons, but all daughters receive the affected X chromosome.
• X-linked dominant traits usually appear in every generation.
• X-linked recessive traits may skip generations through carrier females.
• X-linked recessive traits are generally more frequent in males.

Sex-limited traits are controlled by genes present in both sexes but expressed only in one sex because of anatomical, physiological, or hormonal differences.

• Example: milk production in cattle is controlled by genes in both males and females, but it is expressed only in females.
• Beard growth is another example that is normally limited to males.

Sex-influenced traits are expressed in both sexes, but the dominance relationship or degree of expression differs between males and females.

• A classic example is pattern baldness in humans.
• Suppose allele causes baldness. It may behave as dominant in males but recessive in females.
• A male with may be bald, while a female with may not be bald.

The major difference is that a sex-limited trait is expressed in only one sex, whereas a sex-influenced trait can be expressed in both sexes but with different inheritance or phenotypic effects.

Probability provides a mathematical method for predicting genetic outcomes. Two important rules are:

• Product rule: The probability of two independent events occurring together is the product of their individual probabilities.

• Sum rule: The probability that either of two mutually exclusive events will occur is the sum of their probabilities.

For a dihybrid cross , the probability of a recessive phenotype for each gene is .

Therefore, the probability of the double recessive phenotype is:

The probability of at least one dominant phenotype can be calculated using the complement rule:

The chi-square test is a statistical method used to determine whether the difference between observed and expected genetic results is due to random sampling or to a real deviation from the proposed hypothesis.

The formula is:

where:

• is the observed number.
• is the expected number.
• The summation is performed for every phenotypic class.

The procedure is:

1. State the null hypothesis, usually that the data fit the expected Mendelian ratio.
2. Calculate expected numbers from the total progeny and proposed ratio.
3. Calculate for each class.
4. Add the values to obtain .
5. Determine degrees of freedom using , where is the number of classes.
6. Compare the calculated value with the table value at the chosen significance level.

If the calculated value is less than the table value, the deviation is not significant and the hypothesis is retained. If it is greater, the hypothesis is rejected.

Expected numbers for a ratio are:

• Dominant phenotype: .
• Recessive phenotype: .

The chi-square calculation is:

There are two phenotypic classes, so:

At the 5% significance level and , the critical value is approximately . Since , the deviation is not significant.

Therefore, the null hypothesis is accepted. The observed data are consistent with the expected Mendelian ratio.

A mutation is a sudden, heritable change in the genetic material of an organism. It may involve a change in a single nucleotide, a gene, a chromosome structure, or the chromosome number.

Mutations are important because:

• They create new alleles and increase genetic variation.
• They provide the raw material for natural selection and evolution.
• They may produce beneficial, harmful, or neutral effects.
• They can help organisms adapt to changing environments.
• They are useful in plant and animal breeding for developing improved varieties.
• They are used in genetic research to determine gene function.
• Some mutations cause inherited disorders and cancers.

Mutations may occur spontaneously through natural errors in DNA replication or may be induced by physical or chemical mutagens. A mutation is heritable only when it occurs in germ-line cells or their precursors.

Mutations can be classified in several ways.

On the basis of origin:

• Spontaneous mutations: Arise naturally from replication errors, spontaneous chemical changes, or transposable elements.
• Induced mutations: Produced experimentally or naturally through exposure to mutagenic agents.

On the basis of the cell affected:

• Somatic mutations: Occur in body cells and are generally not transmitted to offspring. They may produce genetic mosaics or contribute to cancer.
• Germinal mutations: Occur in reproductive cells or their precursors and can be inherited by the next generation.

On the basis of genetic organization:

• Gene or point mutations: Affect one or a few nucleotides.
• Chromosomal structural mutations: Include deletion, duplication, inversion, and translocation.
• Genomic mutations: Involve changes in chromosome number, such as aneuploidy or polyploidy.

Mutations may also be classified as beneficial, harmful, or neutral according to their effects on fitness.

Gene mutations are changes in the DNA sequence of a gene.

• Base substitution: One nucleotide pair is replaced by another.
• Transition: A purine replaces a purine or a pyrimidine replaces a pyrimidine.
• Transversion: A purine replaces a pyrimidine or vice versa.
• Insertion: One or more nucleotide pairs are added to the DNA sequence.
• Deletion: One or more nucleotide pairs are removed.

According to their effect on the encoded protein:

• Silent mutation: Changes a codon but does not change the amino acid because of the degeneracy of the genetic code.
• Missense mutation: Changes a codon so that a different amino acid is incorporated.
• Nonsense mutation: Changes a codon into a stop codon, causing premature termination of translation.
• Frameshift mutation: Insertion or deletion of a number of nucleotides that is not a multiple of three shifts the reading frame and usually alters all downstream codons.

The severity depends on the location of the mutation and its effect on protein structure and function.

Chromosomal mutations are changes in chromosome structure caused by chromosome breakage and incorrect rejoining.

• Deletion: A chromosome segment is lost. It may cause loss of genes, haploinsufficiency, or pseudodominance.
• Duplication: A chromosome segment is repeated. It increases gene dosage and provides genetic material that may diverge during evolution.
• Inversion: A segment breaks, rotates by , and rejoins. Inversions may be paracentric, excluding the centromere, or pericentric, including the centromere.
• Translocation: A segment moves to a nonhomologous chromosome. It may be reciprocal or nonreciprocal.

Consequences can include:

• Abnormal gene dosage.
• Disruption of genes at breakpoints.
• Production of abnormal gametes during meiosis.
• Reduced fertility.
• Developmental abnormalities.
• Cancer when a translocation activates an oncogene or creates a fusion gene.

Balanced rearrangements may produce no obvious phenotype in the carrier but can lead to unbalanced chromosome complements in offspring.

Genomic mutations involve changes in the number of complete chromosomes or chromosome sets.

Aneuploidy is the gain or loss of one or more individual chromosomes rather than an entire set.

• Monosomy: .
• Trisomy: .
• Nullisomy: .

Aneuploidy usually results from nondisjunction during meiosis, when homologous chromosomes or sister chromatids fail to separate. In humans, trisomy 21 causes Down syndrome, while monosomy X causes Turner syndrome.

Polyploidy is the presence of three or more complete chromosome sets.

• Triploidy: .
• Tetraploidy: .

Polyploidy may result from chromosome doubling or the fusion of unreduced gametes. It is common and often important in plants because it can produce larger organs, increased vigor, and new species. Aneuploidy is frequently harmful, whereas polyploidy can be advantageous in plant evolution and crop improvement.

Mutation induction involves exposing cells, tissues, seeds, or organisms to agents that increase the mutation rate. The major methods are:

• Physical mutagenesis: Exposure to ultraviolet radiation, X-rays, gamma rays, or other ionizing radiation. These may cause thymine dimers, strand breaks, deletions, or chromosome rearrangements.
• Chemical mutagenesis: Treatment with chemicals such as ethyl methanesulfonate, nitrous acid, hydroxylamine, or base analogues. These may cause base substitutions or abnormal pairing.
• Biological mutagenesis: Use of transposable elements, certain viruses, or mobile genetic elements that insert into genes and disrupt their function.
• In vitro mutagenesis: DNA is altered in a test tube using designed primers, enzymes, or synthetic oligonucleotides and then introduced into cells.
• Site-directed mutagenesis: A specific nucleotide or codon is deliberately changed to study gene function or produce a desired protein.

After treatment, organisms are screened or selected to identify useful mutations.

Mutagenic agents are factors that increase the frequency of mutations. They are classified as follows:

• Physical mutagens: Ultraviolet rays, X-rays, gamma rays, cosmic rays, and high temperature.
• Chemical mutagens: Base analogues, alkylating agents, deaminating agents, intercalating agents, oxidizing agents, and substances that form DNA adducts.
• Biological mutagens: Transposable elements, certain viruses, and some microorganisms or their products.

Their effects include:

• Ultraviolet radiation forms pyrimidine dimers, which interfere with DNA replication and transcription.
• Ionizing radiation produces free radicals and DNA strand breaks.
• Alkylating agents add alkyl groups to bases, leading to mispairing.
• Deaminating agents change the chemical identity of bases.
• Base analogues resemble normal bases but pair abnormally.
• Intercalating agents insert between adjacent base pairs and often cause insertions or deletions.
• Oxidizing agents produce modified bases and strand damage.

Cells repair some damage, but unrepaired changes may become permanent mutations.

Different mutagens induce mutations through different molecular mechanisms.

Ultraviolet radiation:

• UV light is absorbed strongly by DNA.
• It causes covalent bonding between adjacent pyrimidines, especially thymine dimers.
• These dimers distort the DNA helix and block replication.
• Error-prone repair or incorrect replication may produce base substitutions.

Ionizing radiation:

• X-rays and gamma rays ionize molecules directly or interact with water to form free radicals.
• These radicals damage bases and produce single- and double-strand breaks.
• Incorrect repair can cause deletions, inversions, translocations, and other chromosome abnormalities.

Ethyl methanesulfonate:

• Ethyl methanesulfonate is an alkylating agent.
• It transfers an ethyl group to DNA bases, commonly producing altered guanine residues.
• Modified bases may pair incorrectly during replication.
• The resulting mutations are often transition substitutions.

The final mutation depends on the dose, exposure time, repair capacity, and cell-cycle stage.

Spontaneous mutations arise without deliberate exposure to a mutagen, whereas induced mutations result from treatment with physical, chemical, or biological mutagens.

The frequency and detection of induced mutations depend on:

• Type and concentration of the mutagen.
• Duration of exposure.
• Sensitivity and repair ability of the organism.
• Stage of the cell cycle.
• Tissue or cell type treated.
• Whether the mutation occurs in somatic or germinal tissue.
• Dominance or recessiveness of the mutation.
• Size of the population screened.
• Availability of phenotypic, biochemical, or molecular screening methods.

A suitable dose must produce useful mutations without causing excessive lethality or sterility.