Principles of Inheritance and Variation

Principles of Inheritance and Variation

Introduction to Genetics

Genetics is the branch of biology that scientifically deals with inheritance and variation of characters from parents to offspring .

• Inheritance: The process by which characters (traits) are passed from parent to progeny; it is the basis of heredity .
• Variation: The degree by which progeny differ from their parents .
  • Early humans (8000-1000 B.C.) recognized sexual reproduction as a cause of variation and exploited it through artificial selection and domestication to breed desirable organisms (e.g., Sahiwal cows) [2, 3].

Mendel’s Laws of Inheritance

Gregor Mendel conducted hybridisation experiments on garden peas from 1856-1863, proposing laws of inheritance .

• He was the first to apply statistical analysis and mathematical logic to biological problems .
• His experiments had a large sampling size and were confirmed across successive generations [4, 5].
• He investigated characters with two opposing traits (e.g., tall/dwarf, yellow/green seeds) .

Experimental Setup

• Mendel used true-breeding pea lines, which show stable trait inheritance through continuous self-pollination .
• He selected 14 true-breeding pea plant varieties, as pairs, differing in one character with contrasting traits .

Table: Contrasting Traits Studied by Mendel in Pea [7, 8]

Inheritance of One Gene (Monohybrid Cross)

Mendel crossed tall and dwarf pea plants to study the inheritance of a single gene .

• F1 Generation: All progeny plants were tall, resembling one parent; the dwarf trait was not seen .
• F2 Generation: Upon self-pollination of F1 plants, dwarf offspring reappeared. The proportion was 1/4 dwarf and 3/4 tall .
• The traits did not blend; offspring were either tall or dwarf .
• In F2, both parental traits were expressed in a 3:1 ratio .

Concepts Introduced by Mendel

• Factors (Genes): Stably passed down, unchanged from parent to offspring through gametes. Genes are units of inheritance containing information for a particular trait .
• Alleles: Genes that code for a pair of contrasting traits; slightly different forms of the same gene .
  • Capital letters for dominant traits (T for Tall), small letters for recessive traits (t for dwarf) .
• Homozygous: Allelic pair of genes are identical (e.g., TT, tt) .
• Heterozygous: Allelic pair of genes are dissimilar (e.g., Tt) .
• Genotype: The genetic composition of an organism (e.g., TT, Tt, tt) .
• Phenotype: The observable descriptive terms for a trait (e.g., tall, dwarf) .
• Dominant Factor: One factor in a dissimilar pair dominates the other and is expressed (e.g., T for tallness) [13, 15].
• Recessive Factor: The factor that is suppressed by the dominant factor and only expressed in the homozygous condition (e.g., t for dwarfness) [13, 15].
• Monohybrid Cross: A cross between parents heterozygous for genes controlling one character (e.g., Tt x Tt) .

Law of Segregation

• When tall and dwarf plants produce gametes via meiosis, alleles of the parental pair separate or segregate from each other, so each gamete receives only one allele [16, 17].
• This segregation is a random process, with a 50% chance for each allele .
• Homozygous parents produce similar gametes; heterozygous parents produce two kinds of gametes in equal proportion .

Punnett Square

• Developed by Reginald C. Punnett, it is a graphical representation to calculate the probability of all possible genotypes of offspring in a genetic cross [18, 19].
• For a monohybrid cross (TT x tt), the F1 (Tt) self-pollinated yields F2 zygotes in genotypes: 1/4 TT, 1/2 Tt, 1/4 tt .
• The phenotypic ratio in F2 for a monohybrid cross (e.g., Tall:Dwarf) is 3:1 .
• The genotypic ratio in F2 for a monohybrid cross is 1:2:1 .

Test Cross

• Used to determine the genotype of an organism showing a dominant phenotype .
• The organism is crossed with the recessive parent instead of self-crossing .
• The progeny analysis helps predict the test organism’s genotype .

Mendel’s Laws of Inheritance

1. Law of Dominance:
   • Characters are controlled by discrete units called factors (genes) .
   • Factors occur in pairs .
   • In a dissimilar pair, one member (dominant) dominates the other (recessive) .
   • Explains the expression of only one parental character in F1 and both in F2, and the 3:1 ratio in F2 .
2. Law of Segregation:
   • Alleles do not show blending; both characters are recovered in F2 .
   • During gamete formation, factors or alleles of a pair segregate from each other, so each gamete receives only one of the two factors .

Deviations from Mendelian Principles

Incomplete Dominance

• F1 phenotype does not resemble either parent but is in-between them .
• Example: Flower colour in dog flower (snapdragon). A cross between true-breeding red (RR) and white (rr) produces pink (Rr) F1 .
• F2 ratio: 1 Red (RR) : 2 Pink (Rr) : 1 White (rr). The genotypic ratio is 1:2:1, but the phenotypic ratio changes from 3:1 to 1:2:1 because the heterozygote (Rr) is distinguishable [26, 27].
• This occurs when the dominant allele is not completely dominant over the recessive allele .

Explanation of Dominance

• A gene contains information for a particular trait, often producing an enzyme for a substrate transformation .
• Normal allele: Produces normal/efficient enzyme .
• Modified allele: May produce a less efficient, non-functional, or no enzyme .
• If the modified allele produces a non-functional or no enzyme, the phenotype depends on the unmodified (functioning) allele, which is then considered dominant . The recessive trait results from the non-functional or absent enzyme .

Co-dominance

• F1 generation resembles both parents .
• Example: ABO blood grouping in humans .
  • Controlled by gene ‘I’ with three alleles: I^A, I^B, and i .
  • I^A and I^B produce slightly different sugars on red blood cell surfaces .
  • Allele ‘i’ produces no sugar .
  • I^A and I^B are completely dominant over ‘i’ .
  • When I^A and I^B are present together, they both express their own types of sugars, resulting in AB blood type – this is co-dominance .
  • Humans, being diploid, possess any two of these three alleles .

Table: Genetic Basis of ABO Blood Groups

• ABO blood grouping is also an example of multiple alleles (more than two alleles governing the same character in a population) .

Pleiotropy

• A single gene can exhibit multiple phenotypic expressions .
• The underlying mechanism is often the gene’s effect on metabolic pathways .
• Example 1: Phenylketonuria in humans. Caused by a single gene mutation for the enzyme phenylalanine hydroxylase, leading to mental retardation and reduced hair/skin pigmentation .
• Example 2: Starch synthesis in pea seeds. Controlled by one gene with two alleles (B and b) .
  • BB homozygotes: produce large starch grains, round seeds .
  • bb homozygotes: lesser efficiency, smaller starch grains, wrinkled seeds .
  • Bb heterozygotes: round seeds (B is dominant for seed shape), but intermediate size starch grains (incomplete dominance for starch grain size) [35, 37].
• Dominance is not an autonomous feature; it depends on the gene product and the chosen phenotype to examine [37, 38].

Inheritance of Two Genes (Dihybrid Cross)

Mendel crossed pea plants differing in two characters, e.g., yellow and round seeds with green and wrinkled seeds .

• F1 Generation: All seeds were yellow and round, indicating yellow colour is dominant over green, and round shape is dominant over wrinkled .
• F2 Generation: Self-hybridising F1 (RrYy) plants produced a phenotypic ratio of 9:3:3:1 [40, 41].
  • 9 Round, Yellow
  • 3 Wrinkled, Yellow
  • 3 Round, Green
  • 1 Wrinkled, Green

Law of Independent Assortment

• When two pairs of traits are combined in a hybrid, the segregation of one pair of characters is independent of the other pair of characters .
• This means alleles for different traits assort independently during gamete formation [43, 44].
• For RrYy, the four types of gametes (RY, Ry, rY, ry) are produced each with a frequency of 25% (1/4th) .

Chromosomal Theory of Inheritance

Mendel’s work remained unrecognised until 1900 due to:

1. Poor communication .
2. Unaccepted concept of discrete, non-blending ‘factors’ in the face of continuous variation .
3. Novel use of mathematics in biology, which was unacceptable to many biologists .
4. No physical proof for ‘factors’ .

• In 1900, de Vries, Correns, and von Tschermak independently rediscovered Mendel’s results .
• Advancements in microscopy led to the discovery of chromosomes (colored bodies) that double and divide during cell division [46, 47].
• By 1902, Walter Sutton and Theodore Boveri noted that the behavior of chromosomes was parallel to the behavior of genes, using chromosome movement to explain Mendel’s laws .
  • They argued that pairing and separation of chromosomes lead to the segregation of factors they carry .
• Chromosomal Theory of Inheritance: Sutton united knowledge of chromosomal segregation with Mendelian principles .
• Key points of parallelism:
  • Chromosomes and genes occur in pairs [49, 50].
  • They segregate during gamete formation, with only one of each pair transmitted to a gamete [49, 50].
  • Independent pairs segregate independently of each other .
  • The two alleles of a gene pair are located on homologous sites on homologous chromosomes .
  • During Anaphase I of meiosis, chromosome pairs align independently at the metaphase plate .

Linkage and Recombination

• Thomas Hunt Morgan experimentally verified the chromosomal theory using the fruit fly, Drosophila melanogaster .
  • Drosophila advantages: simple synthetic medium, 2-week life cycle, large progeny, clear sex differentiation, observable hereditary variations [52, 53].
• Morgan’s dihybrid crosses in Drosophila (e.g., yellow-bodied, white-eyed females x brown-bodied, red-eyed males) showed that genes did not always segregate independently, and F2 ratios deviated significantly from 9:3:3:1 [53, 54].
• This deviation occurred when two genes were situated on the same chromosome .
  • Linkage: The physical association of genes on a chromosome . When genes are linked, parental gene combinations are much higher than non-parental types .
  • Recombination: The generation of non-parental gene combinations .
• Some genes are tightly linked (low recombination, e.g., white and yellow showed 1.3%) .
• Other genes are loosely linked (higher recombination, e.g., white and miniature wing showed 37.2%) .
• Morgan’s student, Alfred Sturtevant, used the frequency of recombination between gene pairs on the same chromosome as a measure of the distance between genes to ‘map’ their position on the chromosome .
• Genetic maps are now extensively used in whole genome sequencing .

Polygenic Inheritance

• Traits controlled by three or more genes [57, 58].
• Show a gradient of occurrence rather than distinct alternatives (e.g., human height, skin colour) [57, 58].
• Involves multiple genes and is influenced by the environment .
• The phenotype reflects the additive contribution of each allele .
• Example: Human skin colour. Assumed to be controlled by three genes (A, B, C).
  • Dominant alleles (A, B, C) for dark skin; recessive alleles (a, b, c) for light skin .
  • AABBCC genotype: darkest skin colour .
  • aabbcc genotype: lightest skin colour .
  • Genotypes with intermediate numbers of dominant and recessive alleles have intermediate skin colour .

Sex Determination

• Early clues came from insect studies .
• Henking (1891) observed a specific nuclear structure, the X body, in 50% of sperm in some insects; later identified as the X-chromosome [60, 61].

Types of Sex Determination Mechanisms

1. XO Type:
   • Found in a large number of insects (e.g., grasshopper) [61, 62].
   • Females have two X chromosomes (XX); males have one X chromosome (XO) .
   • Eggs bear an X-chromosome; some sperm bear X, some do not [61, 62].
   • Sperm with X fertilise to form females; sperm without X fertilise to form males .
   • Males have half the number of X chromosomes compared to females .
2. XY Type:
   • Found in many insects and mammals, including humans and Drosophila [63, 64].
   • Males have an X and a distinctly smaller Y chromosome (XY); females have a pair of X chromosomes (XX) [63, 64].
   • Both males and females have the same number of autosomes .
3. ZW Type (Female Heterogamety):
   • Found in organisms like birds .
   • Total chromosome number is the same in males and females .
   • Females produce two different types of gametes based on sex chromosomes (Z and W); males produce one type (ZZ) [65, 66].
   • Females are ZW; males are ZZ .

Sex Determination in Humans

• XY type .
• Humans have 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes .
• Females: 22 autosome pairs + XX .
• Males: 22 autosome pairs + XY .
• During spermatogenesis, males produce two types of sperm: 50% carry X-chromosome, 50% carry Y-chromosome .
• Females produce only one type of ovum: carrying an X-chromosome .
• Sperm determines the sex of the child:
  • Ovum (X) + Sperm (X) = Female (XX) .
  • Ovum (X) + Sperm (Y) = Male (XY) .
• There is a 50% probability of either a male or female child in each pregnancy .

Sex Determination in Honey Bee

• Based on the number of sets of chromosomes an individual receives (haplodiploid system) [69, 70].
• Females (Queen or Worker): Develop from fertilised eggs (union of sperm and egg); they are diploid (32 chromosomes) [69, 70].
• Males (Drone): Develop from unfertilised eggs via parthenogenesis; they are haploid (16 chromosomes) [69, 70].
• Unique characteristics of males:
  • Produce sperm by mitosis .
  • Do not have a father .
  • Cannot have sons .
  • Have a grandfather .
  • Can have grandsons .

Mutation

• A phenomenon resulting in alteration of DNA sequences, leading to changes in genotype and phenotype .
• Along with recombination, it is a source of DNA variation .
• Chromosomal aberrations: Loss (deletions) or gain (insertion/duplication) of a DNA segment, resulting in altered chromosomes. Commonly observed in cancer cells .
• Point mutation: Change in a single base pair of DNA .
  • Classical example: Sickle cell anaemia .
• Frame-shift mutations: Caused by deletions and insertions of base pairs .
• Mutagens: Chemical and physical factors that induce mutations (e.g., UV radiations) .

Genetic Disorders

Broadly classified into Mendelian disorders and Chromosomal disorders .

Pedigree Analysis

• The study of family history about inheritance of a particular trait over several generations .
• Provides a tool to trace the inheritance of specific traits, abnormalities, or diseases in human genetics .

Mendelian Disorders

• Mainly determined by alteration or mutation in a single gene .
• Their inheritance pattern can be traced by pedigree analysis .
• May be dominant or recessive, and can be linked to sex chromosomes (e.g., X-linked recessive) .
• Examples: Haemophilia, Cystic fibrosis, Sickle-cell anaemia, Colour blindness, Phenylketonuria, Thalassemia .

1. Colour Blindness:

   • Sex-linked recessive disorder .
   • Defect in red or green cones of the eye, causing failure to discriminate between red and green colour .
   • Due to mutation in genes on the X chromosome .
   • Occurs in about 8% of males and 0.4% of females .
   • Males have only one X chromosome, so they express the trait if they inherit the recessive gene .
   • Females are usually carriers if heterozygous (their normal dominant gene suppresses the recessive one) .

2. Haemophilia:

   • Sex-linked recessive disease .
   • Transmission from unaffected carrier female to some male progeny .
   • Affects a single protein involved in blood clotting cascade, leading to non-stop bleeding from simple cuts .
   • Heterozygous females are carriers .
   • A female becoming haemophilic is extremely rare (mother must be a carrier, father haemophilic) .
   • Queen Victoria’s family pedigree shows haemophilic descendants .

3. Sickle-cell Anaemia:

   • Autosome-linked recessive trait .
   • Transmitted when both parents are carriers (heterozygous) .
   • Controlled by a single pair of alleles: Hb^A and Hb^S .
   • Homozygous individuals for Hb^S (Hb^SHb^S) show the diseased phenotype .
   • Heterozygous (Hb^AHb^S) individuals are apparently unaffected but are carriers (50% chance of transmitting mutant gene) .
   • Defect: Substitution of Glutamic acid (Glu) by Valine (Val) at the sixth position of the beta globin chain of the haemoglobin molecule .
   • This is due to a single base substitution at the sixth codon of the beta globin gene from GAG to GUG .
   • Mutant haemoglobin polymerises under low oxygen tension, changing RBC shape from biconcave disc to elongated sickle-like .

4. Phenylketonuria:

   • Autosomal recessive trait and an inborn error of metabolism .
   • Affected individuals lack an enzyme that converts phenylalanine into tyrosine .
   • Phenylalanine accumulates and is converted into phenylpyruvic acid and other derivatives .
   • Accumulation in the brain leads to mental retardation .
   • Excreted through urine due to poor kidney absorption .

5. Thalassemia:

   • Autosome-linked recessive blood disease .
   • Transmitted when both parents are unaffected carriers .
   • Caused by mutation or deletion, leading to reduced rate of synthesis of one of the globin chains (alpha or beta) that make up haemoglobin .
   • Results in abnormal haemoglobin molecules and anaemia .
   • α Thalassemia: Affects α globin chain production; controlled by two linked genes (HBA1, HBA2) on chromosome 16. More affected genes mean less alpha globin .
   • β Thalassemia: Affects β globin chain production; controlled by a single gene (HBB) on chromosome 11. Occurs due to mutation of one or both genes .
   • Difference from sickle-cell anaemia: Thalassemia is a quantitative problem (too few globin molecules), while sickle-cell anaemia is a qualitative problem (incorrectly functioning globin) .

Chromosomal Disorders

• Caused by the absence, excess, or abnormal arrangement of one or more chromosomes .
• Aneuploidy: Gain or loss of a chromosome(s) due to failure of chromatid segregation during cell division .
  • Trisomy: Gain of an extra copy of a chromosome (e.g., trisomy of chromosome 21 in Down’s syndrome) [84, 85].
  • Monosomy: Loss of one of any one pair of chromosomes (e.g., loss of an X chromosome in Turner’s syndrome) [84, 85].
• Polyploidy: Increase in a whole set of chromosomes, often seen in plants, due to failure of cytokinesis after telophase .
• Normal human cells have 46 chromosomes (23 pairs): 22 autosome pairs + 1 sex chromosome pair .

1. Down’s Syndrome:

   • Caused by the presence of an additional copy of chromosome 21 (Trisomy 21) .
   • First described by Langdon Down (1866) .
   • Symptoms: Short stature, small round head, furrowed tongue, partially open mouth, broad palm with characteristic palm crease, retarded physical, psychomotor, and mental development .

2. Klinefelter’s Syndrome:

   • Caused by the presence of an additional X-chromosome, resulting in a karyotype of 47, XXY .
   • Symptoms: Overall masculine development with expression of feminine development (e.g., development of breasts, Gynaecomastia), individuals are sterile .

3. Turner’s Syndrome:

   • Caused by the absence of one of the X chromosomes, resulting in a karyotype of 45, X0 .
   • Symptoms: Females are sterile (rudimentary ovaries), lack other secondary sexual characters, short stature .