Principles of Inheritance and Variation

Accumulation Of Variation During Reproduction

Reproduction, whether sexual or asexual, is the process by which organisms produce offspring. A key aspect of reproduction is the transmission of traits from parents to offspring. However, this transmission is not always exact, leading to variations.

Variation in Asexual vs. Sexual Reproduction:

• Asexual Reproduction: Involves a single parent producing offspring that are genetically identical clones of the parent. Variations in asexual reproduction are minimal and mainly arise from random errors during DNA replication (mutations). These variations accumulate slowly over generations.
• Sexual Reproduction: Involves the fusion of gametes (from one or usually two parents). The offspring are not genetically identical to the parents or each other. Variations are significant and arise from several processes:
  • Mutations: Changes in the DNA sequence.
  • Recombination: Exchange of genetic material between homologous chromosomes during meiosis (crossing over). This creates new combinations of alleles on the chromosomes.
  • Independent Assortment: Random orientation and separation of homologous chromosomes during meiosis I, leading to different combinations of chromosomes in the gametes.
  • Random Fertilisation: The random fusion of any male gamete with any female gamete from the parental pool.

Accumulation of Variations:

• Variations are accumulated over successive generations.
• In asexually reproducing populations, variations are fewer and accumulate slower.
• In sexually reproducing populations, variations are more numerous and accumulate faster. Each generation is a new combination of genes from the previous generation, further shuffled by recombination and independent assortment.

Significance of Accumulated Variations:

• Adaptation: Variations provide the raw material for adaptation to changing environments. Individuals with favourable variations are selected by natural selection and survive and reproduce better.
• Evolution: The accumulation and selection of variations over long periods lead to the process of evolution and the formation of new species.

The process of reproduction, while ensuring species continuity, is also the engine of variation, which is fundamental to the diversity of life and evolution.

Heredity

Heredity is the phenomenon of transmission of characters (traits) from parents to offspring. It is also known as inheritance.

The study of heredity and variation is called Genetics. Genetics is the branch of biology that deals with inheritance, as well as the variation of inherited characters.

Inherited Traits

Inherited traits are characteristics that are passed down from parents to offspring. These traits are determined by genes.

Examples of inherited traits in humans: Eye colour, hair colour, height, blood group, certain predispositions to diseases.

Rules For The Inheritance Of Traits – Mendel’s Contributions

The fundamental principles of inheritance were first established by Gregor Johann Mendel, an Austrian monk, in the mid-19th century. Mendel conducted hybridisation experiments on garden peas ($Pisum \: sativum$) for seven years (1856-1863) and proposed laws of inheritance.

Why Mendel Chose Pea Plants:

• Pea plants are easy to cultivate.
• They have a relatively short life cycle.
• They have well-defined, easily observable contrasting characters (traits).
• They can be self-pollinated (pure lines can be obtained) and cross-pollinated easily.
• They produce a large number of seeds in each generation.

Mendel's Experimental Approach:

• Mendel studied the inheritance of one trait at a time (monohybrid cross) or two traits at a time (dihybrid cross).
• He selected 7 pairs of contrasting characters in pea plants:
  • Stem height (Tall/Dwarf)
  • Flower colour (Violet/White)
  • Flower position (Axial/Terminal)
  • Pod shape (Inflated/Constricted)
  • Pod colour (Green/Yellow)
  • Seed shape (Round/Wrinkled)
  • Seed colour (Yellow/Green)
• He started with pure lines (true-breeding varieties) for these traits (e.g., plants that always produced tall offspring when self-pollinated for several generations).
• He performed cross-pollination between plants with contrasting traits (P generation - parental generation).
• He grew the seeds from these crosses and observed the traits in the first filial generation (F$_1$ generation).
• He then allowed the F$_1$ plants to self-pollinate and observed the traits in the second filial generation (F$_2$ generation).
• Mendel analysed the results statistically, counting the number of offspring showing each trait.

Mendel's meticulous experimental design and statistical analysis were key to his success.

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How Do These Traits Get Expressed?

Mendel's work led to the concept of factors (now called genes) that control traits and are passed from parents to offspring.

Genes and Alleles:

• Gene: A unit of inheritance. A segment of DNA that codes for a specific trait or function.
• Alleles: Different forms of the same gene. For example, the gene for stem height in pea plants has two alleles: one for Tallness and one for Dwarfness.
• For a given trait, a diploid organism has two alleles, one inherited from each parent.

Dominance and Recessiveness:

• Mendel observed that in a pair of contrasting traits, one trait would be expressed in the F$_1$ generation, while the other was suppressed.
• The trait that is expressed is called the dominant trait (or dominant allele).
• The trait that is suppressed in the F$_1$ generation but reappears in the F$_2$ generation is called the recessive trait (or recessive allele).
• Dominant alleles are often represented by a capital letter (e.g., 'T' for tallness), and recessive alleles by the corresponding small letter (e.g., 't' for dwarfness).

Genotype and Phenotype:

• Genotype: The genetic makeup of an organism, i.e., the set of alleles it possesses for a particular trait (e.g., TT, Tt, tt).
• Phenotype: The observable physical or biochemical characteristic of an organism, determined by its genotype and environment (e.g., Tall, Dwarf).

For the height trait in peas:

• Genotype TT: Phenotype Tall (homozygous dominant)
• Genotype Tt: Phenotype Tall (heterozygous) - because Tall is dominant over Dwarf
• Genotype tt: Phenotype Dwarf (homozygous recessive)

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Sex Determination (Brief Introduction):

While Mendel's work primarily focused on autosomal traits, the concept of inherited factors also applies to traits determining the sex of an individual. Sex determination is the biological system that determines whether an organism develops as a male or a female.

In many organisms, sex is determined by specific chromosomes called sex chromosomes (e.g., X and Y chromosomes in humans).

Mendel’S Laws Of Inheritance

Based on his experiments on pea plants, particularly the monohybrid and dihybrid crosses, Mendel proposed certain principles or laws of inheritance. These laws are fundamental to genetics.

Mendel's Laws:

1. Law of Dominance:
   • States that when parents with pure, contrasting traits are crossed, only one form of the trait (the dominant trait) will appear in the next generation (F$_1$ generation). The other trait (the recessive trait) is masked.
   • In a pair of dissimilar alleles, one allele (dominant) expresses itself, while the other allele (recessive) is masked.
2. Law of Segregation (Law of Purity of Gametes):
   • States that during the formation of gametes, the two alleles for a character separate or segregate from each other such that each gamete receives only one allele for that character.
   • These alleles remain 'pure' during segregation and do not blend.
   • This law is universal and applies to all sexually reproducing organisms.
3. Law of Independent Assortment:
   • States that when two pairs of traits (genes) are combined in a hybrid, segregation of one pair of characters is independent of the other pair of characters.
   • This law applies to the inheritance of two or more traits simultaneously. The alleles of different genes sort independently into gametes during meiosis.

Mendel's first two laws (Law of Dominance and Law of Segregation) can be understood from the results of a monohybrid cross, while the Law of Independent Assortment is derived from the results of a dihybrid cross.

Answer:

Inheritance Of One Gene

Studying the inheritance of a single gene or trait at a time is called a monohybrid cross. Mendel's monohybrid crosses formed the basis for his first two laws.

Monohybrid Cross:

Consider Mendel's experiment with stem height: He crossed a pure tall pea plant (TT) with a pure dwarf pea plant (tt).

• Parental generation (P): TT $\times$ tt
• Gametes: T (from TT) and t (from tt)
• F$_1$ generation: All Tt (heterozygous). All plants were Tall. (This demonstrated the Law of Dominance).
• F$_1$ selfing: Tt $\times$ Tt
• Gametes from F$_1$: Both Tt plants produce two types of gametes: T and t (in equal proportions, due to segregation of alleles).
• F$_2$ generation: Offspring produced by random fusion of these gametes:
  • TT (25%) - Homozygous Tall
  • Tt (50%) - Heterozygous Tall
  • tt (25%) - Homozygous Dwarf
• F$_2$ Genotypic Ratio: 1 : 2 : 1 (TT : Tt : tt)
• F$_2$ Phenotypic Ratio: 3 : 1 (Tall : Dwarf)

The reappearance of the dwarf phenotype (tt) in the F$_2$ generation, even though it was not seen in the F$_1$, supports the idea that alleles segregate during gamete formation and retain their identity (Law of Segregation).

*(Image shows a diagram of a monohybrid cross, including P genotypes, gametes, F1 genotype/phenotype, F1 selfing, F2 genotypes/phenotypes, and the typical 3:1 phenotypic ratio)*

Law Of Dominance

Already discussed above (see Section I3). This law explains why one trait appears and the other is masked in the F$_1$ generation when crossing contrasting homozygous parents. It also explains the 3:1 phenotypic ratio observed in the F$_2$ generation of a monohybrid cross.

Law Of Segregation

Already discussed above (see Section I3). This law is based on the fact that alleles do not blend and that both alleles of a pair are recovered in the F$_2$ generation, even if one is masked in the F$_1$. The segregation of alleles is a random process.

Test Cross:

A test cross is a cross between an individual with a dominant phenotype (but unknown genotype - could be homozygous dominant TT or heterozygous Tt) and a homozygous recessive individual (tt).

• Purpose: To determine the genotype of the individual showing the dominant phenotype.
• If the unknown individual is homozygous dominant (TT), all offspring of the test cross will be heterozygous (Tt) and show the dominant phenotype (Tall). Phenotypic ratio 1:0 (Tall:Dwarf).
• If the unknown individual is heterozygous (Tt), the offspring of the test cross will be 50% heterozygous (Tt) and 50% homozygous recessive (tt). Phenotypic ratio 1:1 (Tall:Dwarf).

*(Image shows diagrams of a test cross, one where the unknown is homozygous dominant and the resulting F1 are all dominant, and one where the unknown is heterozygous and the resulting F1 show a 1:1 ratio)*

Incomplete Dominance

Incomplete dominance is a type of inheritance where the heterozygous genotype results in a phenotype that is intermediate between the phenotypes of the two homozygous parents. Neither allele is completely dominant over the other.

• Example: Flower colour in Snapdragon ($Antirrhinum \: majus$) or Four o'clock plant ($Mirabilis \: jalapa$).
• Cross: Homozygous Red flowered plant (RR) $\times$ Homozygous White flowered plant (rr)
• F$_1$ generation: All Rr. Phenotype is Pink flowers (intermediate).
• F$_1$ selfing: Rr $\times$ Rr
• F$_2$ generation: RR (Red), Rr (Pink), rr (White).
  • Genotypic Ratio: 1 : 2 : 1 (RR : Rr : rr)
  • Phenotypic Ratio: 1 : 2 : 1 (Red : Pink : White)

In incomplete dominance, the phenotypic ratio in the F$_2$ generation is the same as the genotypic ratio.

*(Image shows a diagram illustrating the cross between red and white flowered plants resulting in pink F1, and selfing of F1 showing 1:2:1 phenotypic ratio of red:pink:white in F2)*

Co-Dominance

Co-dominance is a type of inheritance where both alleles in a heterozygote are fully expressed, resulting in a phenotype that shows characteristics of both homozygous parents.

• Example: ABO blood groups in humans.
• Blood groups are determined by the gene I, which has three alleles: $I^A, I^B, i$.
• $I^A$ and $I^B$ are dominant over $i$.
• $I^A$ and $I^B$ are co-dominant to each other.
• Genotypes and Phenotypes:
  • $I^A I^A$: Blood group A
  • $I^A i$: Blood group A
  • $I^B I^B$: Blood group B
  • $I^B i$: Blood group B
  • $I^A I^B$: Blood group AB (Both A and B antigens are expressed on RBCs - co-dominance)
  • $ii$: Blood group O

Co-dominance differs from incomplete dominance because in co-dominance, both alleles are expressed, not an intermediate phenotype.

Answer:

Inheritance Of Two Genes

Studying the inheritance of two different genes or traits simultaneously in a cross is called a dihybrid cross. Mendel's dihybrid crosses led to his third law.

Dihybrid Cross:

Consider Mendel's experiment with seed shape (Round/Wrinkled) and seed colour (Yellow/Green). Round (R) is dominant over wrinkled (r), and Yellow (Y) is dominant over green (y).

• Parental generation (P): Pure Round, Yellow (RRYY) $\times$ Pure Wrinkled, Green (rryy)
• Gametes: RY (from RRYY) and ry (from rryy)
• F$_1$ generation: All RrYy (heterozygous for both traits). Phenotype: All Round, Yellow. (Demonstrates Law of Dominance for both traits).
• F$_1$ selfing: RrYy $\times$ RrYy
• Gametes from F$_1$: Each parent produces four types of gametes due to independent assortment of alleles: RY, Ry, rY, ry (in equal proportions 1:1:1:1).
• F$_2$ generation: Produced by random fusion of these 4 types of gametes from each parent (using a 4x4 Punnett Square).
• F$_2$ Phenotypes and Ratio: Mendel observed four phenotypic categories in the F$_2$ generation:
  • Round, Yellow
  • Round, Green
  • Wrinkled, Yellow
  • Wrinkled, Green

  The phenotypic ratio observed was approximately 9 : 3 : 3 : 1.

  • 9/16 Round, Yellow (R_Y_)
  • 3/16 Round, Green (R_yy)
  • 3/16 Wrinkled, Yellow (rrY_)
  • 1/16 Wrinkled, Green (rryy)

*(Image shows a diagram of a dihybrid cross, including P genotypes, gametes, F1 genotype/phenotype, Punnett square for F1 selfing showing the 9:3:3:1 phenotypic ratio in F2)*

Law Of Independent Assortment

Already discussed above (see Section I3). The 9:3:3:1 phenotypic ratio observed in the dihybrid cross supports this law. It shows that the inheritance of seed shape is independent of the inheritance of seed colour, and vice versa. For example, Round shape can be inherited with either Yellow or Green colour, and Wrinkled shape can also be inherited with either Yellow or Green colour.

This law applies when the genes for the two traits are located on different chromosomes or are far apart on the same chromosome.

Chromosomal Theory Of Inheritance

Mendel's work was rediscovered in 1900 by De Vries, Correns, and von Tschermak. Around the same time, with advancements in microscopy, chromosomes were observed during cell division.

In 1902, Walter Sutton and Theodore Boveri proposed the Chromosomal Theory of Inheritance. This theory states that:

• Genes (Mendel's 'factors') are located on chromosomes.
• Chromosomes occur in homologous pairs in diploid organisms.
• Homologous chromosomes segregate during meiosis.
• Pairs of homologous chromosomes assort independently during meiosis.

The behaviour of chromosomes during meiosis is parallel to the behaviour of genes as described by Mendel's laws. This theory provided a physical basis for the laws of inheritance.

Linkage And Recombination

Mendel's Law of Independent Assortment holds true for genes located on different chromosomes. However, if two genes are located on the same chromosome, their inheritance is often not independent. This phenomenon is called linkage.

• Linkage: The tendency of genes located on the same chromosome to be inherited together. These genes are called linked genes.
• Linked genes do not assort independently.
• The strength of linkage depends on the distance between the genes on the chromosome. Genes located closer together are more tightly linked and less likely to be separated.

Morgan's Experiments on Fruit Flies (Drosophila melanogaster):

• Thomas Hunt Morgan studied linkage using fruit flies. He chose Drosophila because they have a short life cycle, produce many offspring, and have distinct observable traits and clear chromosomes (only 4 pairs).
• Morgan conducted dihybrid crosses with genes located on the same chromosome (e.g., genes for body colour and wing size on the X chromosome).
• He observed that the phenotypic ratios in the F$_2$ generation of such crosses deviated significantly from Mendel's expected 9:3:3:1 ratio, with parental combinations appearing more frequently. This was due to linkage.

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Recombination (Crossing Over):

• Even when genes are linked, new combinations of alleles can be formed due to crossing over (exchange of segments between homologous chromosomes) during meiosis. This process is called recombination.
• Crossing over occurs with a certain frequency between linked genes. The frequency of recombination between two genes is directly proportional to the distance between them on the chromosome.
• Alfred Sturtevant, a student of Morgan, used the frequency of recombination to measure the distance between genes and construct genetic maps.

Linkage and recombination explain the deviations from the Law of Independent Assortment and provided evidence that genes are indeed located linearly on chromosomes.

Polygenic Inheritance

In addition to the inheritance of traits controlled by a single gene (monogenic inheritance), some traits are controlled by multiple genes. This is known as polygenic inheritance or quantitative inheritance.

Characteristics of Polygenic Inheritance:

• The trait is controlled by two or more genes.
• Multiple genes contribute to the phenotype, often with each gene having a small additive effect.
• The phenotype often shows a continuous range of variation rather than distinct categories.
• The effect of the environment can influence the phenotype.

Example: Human skin colour. Skin colour is controlled by three or more gene loci. Each gene contributes to the amount of melanin produced. Individuals with more 'dark' alleles will have darker skin. The variation in skin colour in a population is continuous, ranging from very light to very dark, with many intermediate shades. This pattern of inheritance results in a bell-shaped (normal) distribution curve when the frequency of phenotypes is plotted.

Other examples: Human height, grain colour in wheat, kernel number in maize.

Polygenic inheritance is contrasted with Mendelian inheritance (monogenic) where a single gene primarily determines a trait, often resulting in discrete phenotypes.

Pleiotropy

While typically one gene controls one trait, in some cases, a single gene can influence multiple phenotypic traits. This phenomenon is called pleiotropy.

In pleiotropy, the product of a single gene affects several apparently unrelated traits. This often happens when the gene product (e.g., an enzyme or a protein) is involved in multiple metabolic pathways or has diverse roles in development.

Example: Phenylketonuria. This is a genetic disorder in humans caused by a mutation in a single gene that codes for the enzyme phenylalanine hydroxylase. This enzyme is required to convert the amino acid phenylalanine into tyrosine.

• Deficiency of this enzyme leads to the accumulation of phenylalanine in the body.
• This accumulation affects several aspects of development, leading to multiple symptoms:
  • Mental retardation (due to build-up in the brain).
  • Reduction in hair and skin pigmentation (phenylalanine is needed for tyrosine synthesis, and tyrosine is a precursor for melanin pigment).

Thus, a single gene mutation leads to multiple phenotypic effects.

Other examples: Sickle cell anaemia (single gene mutation affects haemoglobin structure, leading to multiple effects like anaemia, susceptibility to infections, organ damage), starch synthesis in pea plants (single gene affects seed shape - Round vs. Wrinkled - and also starch grain size).

Pleiotropy shows the complex relationship between genotype and phenotype, where a single genetic change can have widespread consequences.

Sex Determination

Sex determination is the biological process that determines whether an organism develops as a male or a female. Various mechanisms of sex determination exist in nature.

Chromosomal Theory of Sex Determination:

In many organisms, sex is determined by specific chromosomes called sex chromosomes, which differ between males and females. The other chromosomes are called autosomes.

• XX-XY type: Found in humans, many mammals, some insects (e.g., Drosophila).
  • Females have two X chromosomes (XX). They are homogametic (produce only one type of gamete with an X chromosome).
  • Males have one X and one Y chromosome (XY). They are heterogametic (produce two types of gametes: 50% with X and 50% with Y).
  • The sex of the offspring is determined by the sperm that fertilises the egg. An egg fertilized by an X-bearing sperm results in a female (XX), and an egg fertilized by a Y-bearing sperm results in a male (XY).
  • The Y chromosome carries the SRY gene (Sex-determining Region on Y), which initiates male development.
• XX-XO type: Found in some insects (e.g., grasshoppers).
  • Females are XX (homogametic).
  • Males are XO (have only one X chromosome, no Y). They are heterogametic (produce 50% gametes with X and 50% gametes without X).
  • Sex is determined by the number of X chromosomes.
• ZW-ZZ type: Found in birds, some reptiles, some insects, fish.
  • Females are ZW (heterogametic, produce gametes with Z or W).
  • Males are ZZ (homogametic, produce only gametes with Z).
  • Sex is determined by the egg. An egg with a Z chromosome fertilised by a Z-bearing sperm results in a male (ZZ). An egg with a W chromosome fertilised by a Z-bearing sperm results in a female (ZW).

Sex Determination In Humans

• Humans follow the XX-XY type of sex determination.
• Females: Karyotype is 44 autosomes + XX. Produce eggs with 22 autosomes + X.
• Males: Karyotype is 44 autosomes + XY. Produce sperm with 22 autosomes + X or 22 autosomes + Y (in roughly equal proportions).
• Fertilisation:
  • Egg (X) + Sperm (X) $\rightarrow$ Zygote (XX) $\rightarrow$ Female offspring.
  • Egg (X) + Sperm (Y) $\rightarrow$ Zygote (XY) $\rightarrow$ Male offspring.
• The sex of the baby is determined by the type of sperm that fertilises the egg. The father is responsible for determining the sex of the child.
• The probability of having a male or female child is 50:50 in each pregnancy.

*(Image shows diagrams illustrating female parent (XX) producing X gametes and male parent (XY) producing X and Y gametes, and a Punnett square showing possible combinations resulting in XX (female) and XY (male) offspring)*

Sex Determination In Honey Bee

Sex determination in honey bees is unusual and is based on the number of sets of chromosomes an individual receives. This is called Haplo-diploid sex determination.

• Females (Queens and Workers): Develop from fertilised eggs. They are diploid (2n = 32 chromosomes), receiving one set of chromosomes from the mother (queen) and one set from the father (drone).
• Males (Drones): Develop from unfertilised eggs. They are haploid (n = 16 chromosomes), receiving only one set of chromosomes from the mother. They are produced by parthenogenesis (development of an egg without fertilisation).
• The queen is diploid and produces eggs by meiosis (haploid eggs).
• The drone is haploid and produces sperm by mitosis (haploid sperm).
• Fertilisation: Egg (n) + Sperm (n) $\rightarrow$ Zygote (2n) $\rightarrow$ Female (Queen or Worker).
• No Fertilisation: Egg (n) $\rightarrow$ Male (Drone).

Sex determination is not based on sex chromosomes but on ploidy level.

Note: Drones (males) do not have fathers (since they develop from unfertilised eggs) but they have grandfathers (since their mother, the queen, developed from a fertilised egg).

Sex determination mechanisms are diverse, reflecting different evolutionary strategies for ensuring reproduction and species survival.

Mutation

Mutation is a sudden heritable change in the genetic material (DNA sequence or chromosome structure/number) of an organism. Mutations are the ultimate source of all genetic variation.

Types of Mutations:

Mutations can be broadly classified based on the scale of the change:

• Gene Mutations (Point Mutations): Changes in the nucleotide sequence of a single gene.
  • Substitution: One nucleotide base is replaced by another. Can lead to silent mutations (no change in amino acid), missense mutations (change in amino acid), or nonsense mutations (introduction of a stop codon). Example: Sickle cell anaemia is caused by a single nucleotide substitution in the beta-globin gene.
  • Insertion/Deletion (Frameshift Mutations): Addition or removal of one or more nucleotides (not in multiples of three) in a gene. This shifts the reading frame of the codons, altering the sequence of amino acids produced downstream of the mutation. Often leads to non-functional proteins.
• Chromosomal Mutations: Changes in the structure or number of chromosomes.
  • Chromosomal Aberrations (Structural changes):
    • Deletion: Loss of a segment of a chromosome.
    • Duplication: Repetition of a segment of a chromosome.
    • Inversion: A segment of a chromosome is flipped 180 degrees.
    • Translocation: Transfer of a segment of a chromosome to a non-homologous chromosome.
  • Change in Chromosome Number:
    • Aneuploidy: Gain or loss of one or a few chromosomes (e.g., Trisomy - gain of one chromosome, Monosomy - loss of one chromosome). Caused by non-disjunction during meiosis. Example: Down's syndrome (Trisomy 21), Turner's syndrome (XO).
    • Polyploidy: Gain of an entire set of chromosomes (e.g., triploid 3n, tetraploid 4n). Common in plants, rare in animals. Can arise from failure of cytokinesis after telophase.

Causes of Mutations:

• Spontaneous Mutations: Occur naturally due to errors during DNA replication, repair, or recombination.
• Induced Mutations: Caused by exposure to external agents called mutagens.
  • Physical mutagens: Ionising radiations (X-rays, gamma rays), UV radiation.
  • Chemical mutagens: Certain chemicals (e.g., alkylating agents, base analogs).

Significance of Mutation:

• Mutations are the ultimate source of new alleles and genetic variation in a population.
• They provide the raw material for evolution.
• While many mutations are harmful, some can be neutral or even beneficial, providing an adaptive advantage.
• Mutations in somatic cells can lead to cancer.
• Mutations in germ cells are heritable and can be passed to offspring, leading to genetic disorders.

Genetic Disorders

Genetic disorders are conditions caused by abnormalities in an individual's genome, which can be caused by mutations in one or a few genes (Mendelian disorders) or by changes in chromosome structure or number (Chromosomal disorders). These disorders are often heritable.

Pedigree Analysis

Pedigree analysis is the study of the inheritance of a particular trait or genetic disorder within a family over several generations. It involves constructing a pedigree chart, which is a diagram representing the family history using standard symbols.

Symbols used in Pedigree Analysis:

• Square: Male
• Circle: Female
• Diamond: Sex unspecified
• Shaded symbol: Affected individual
• Unshaded symbol: Unaffected individual
• Horizontal line between parents: Marriage/Mating
• Vertical line from parents: Offspring
• Siblings are connected by a horizontal line above them.
• Generations are represented by Roman numerals (I, II, III...).
• Individuals within a generation are numbered (1, 2, 3...).

Pedigree analysis helps determine the mode of inheritance of a trait (e.g., autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive) and predict the probability of offspring being affected.

*(Image shows a sample pedigree chart illustrating how generations and individuals are represented, showing affected and unaffected males/females, and marriages/offspring)*

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Mendelian Disorders

Mendelian disorders are genetic diseases caused by a mutation in a single gene. They follow the principles of Mendelian inheritance (Law of Dominance, Segregation, Independent Assortment).

They are classified based on whether the gene is located on an autosome or a sex chromosome and whether the allele causing the disorder is dominant or recessive.

• Autosomal Dominant: Caused by a dominant allele on an autosome. Only one copy of the dominant allele is needed for the disorder to appear. Affected individuals usually have at least one affected parent. Trait appears in every generation.

  Example: Myotonic dystrophy, Huntington's disease.

• Autosomal Recessive: Caused by a recessive allele on an autosome. Two copies of the recessive allele are needed for the disorder to appear. Unaffected individuals can be carriers (heterozygous). Affected individuals may have unaffected parents (who are carriers). Trait may skip generations.

  Example: Phenylketonuria, Cystic fibrosis, Sickle-cell anaemia, Thalassemia, Albinism.

• X-linked Dominant: Caused by a dominant allele on the X chromosome. Affected fathers pass the trait to all their daughters but none of their sons. Affected heterozygous mothers pass the trait to half their sons and half their daughters. Less common.

  Example: Hypophosphatemic rickets.

• X-linked Recessive: Caused by a recessive allele on the X chromosome. More common in males (who have only one X chromosome). Affected males pass the allele to all their daughters (who become carriers) but none of their sons. Carrier mothers have a 50% chance of having an affected son and a 50% chance of having a carrier daughter.

  Example: Haemophilia, Colour blindness.

• Y-linked Inheritance: Genes on the Y chromosome are only passed from father to son. Very few genes on the Y chromosome, mainly related to male fertility.

  Example: Some forms of male infertility.

Examples of Mendelian Disorders in detail:

• Phenylketonuria: (Autosomal recessive) Metabolic disorder. Deficiency of enzyme phenylalanine hydroxylase, leading to accumulation of phenylalanine and mental retardation.
• Sickle-cell Anaemia: (Autosomal recessive) Disorder of blood. Caused by a single nucleotide substitution in the beta-globin gene, leading to abnormal haemoglobin (HbS). HbS causes RBCs to become sickle-shaped under low oxygen conditions, blocking blood vessels and causing anaemia and pain. Heterozygous carriers ($Hb^A Hb^S$) are resistant to malaria.
• Thalassemia: (Autosomal recessive) Disorder of blood. Reduced synthesis of alpha or beta globin chains of haemoglobin, leading to anaemia. Different types depending on which globin chain is affected.
• Haemophilia: (X-linked recessive) Bleeding disorder. Deficiency of clotting factors (Factor VIII or IX), causing prolonged bleeding even from minor cuts. More common in males.
• Colour Blindness: (X-linked recessive) Inability to distinguish certain colours (most commonly red and green). Genes for red and green cone pigments are on the X chromosome. More common in males.

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Chromosomal Disorders

Chromosomal disorders are caused by abnormalities in the structure or number of chromosomes. These arise due to errors during cell division (e.g., non-disjunction).

• Aneuploidy: Gain or loss of one or more chromosomes.
  • Down's Syndrome: (Trisomy 21) Presence of an extra copy of chromosome 21. Individuals have characteristic facial features, intellectual disability, short stature, and other health problems.
  • Turner's Syndrome: (Monosomy X, 45, XO) Absence of one X chromosome in females. Individuals are sterile females with underdeveloped reproductive organs, short stature, webbed neck.
  • Klinefelter's Syndrome: (Trisomy XXY, 47, XXY) Presence of an extra X chromosome in males. Individuals are males with overall masculine development, but often show feminine characteristics (e.g., gynaecomastia), are sterile.
• Structural Chromosomal Abnormalities: (Deletion, Duplication, Inversion, Translocation) Can also lead to genetic disorders, but aneuploidy is more commonly discussed as a distinct category of chromosomal disorders.

Genetic counselling, prenatal diagnosis, and genetic testing are important tools for identifying and managing genetic disorders in families. While many genetic disorders are currently incurable, research continues to develop therapies, including gene therapy.