Mendel’S Laws Of Inheritance

The study of inheritance and variation forms the basis of Genetics, a branch of biology. Inheritance is the process by which characteristics are passed from parents to offspring, forming the foundation of heredity. Variation describes the differences observed between offspring and their parents, and among siblings.

Early human societies, dating back to $8000-1000$ B.C., had a practical understanding of inheritance and variation, particularly recognising that sexual reproduction contributes to variation. They used this knowledge in selective breeding of plants and animals to cultivate desirable traits, leading to the development of domesticated varieties like the Sahiwal cows from wild ancestors.

However, the scientific basis of inheritance remained largely unknown until the mid-19th century.

Gregor Mendel, an Austrian monk, is considered the 'Father of Genetics'. He conducted hybridisation experiments on garden pea plants (Pisum sativum) for seven years (1856-1863). His work was groundbreaking for several reasons:

• He applied statistical analysis and mathematical logic to biological problems for the first time.
• He used a large sample size, which made his data more reliable.
• He conducted experiments on successive generations (F1, F2, etc.), which helped confirm his findings and establish general rules of inheritance.
• He studied characters that had distinct contrasting traits (e.g., tall/dwarf, yellow/green seeds), which simplified the analysis.

Mendel performed artificial pollination/cross-pollination using several true-breeding pea lines. A true-breeding line is one that consistently shows the same trait expression over several generations when self-pollinated.

He selected 14 true-breeding varieties, focusing on 7 pairs of contrasting traits.

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S.No.	Character	Contrasting Traits
1.	Stem height	Tall/dwarf
2.	Flower colour	Violet/white
3.	Flower position	Axial/terminal
4.	Pod shape	Inflated/constricted
5.	Pod colour	Green/yellow
6.	Seed shape	Round/wrinkled
7.	Seed colour	Yellow/green

Inheritance Of One Gene

Mendel studied the inheritance of a single character by crossing true-breeding plants that differed in only one trait. This is called a monohybrid cross.

Example: Crossing a true-breeding tall pea plant with a true-breeding dwarf pea plant.

Steps:

1. Mendel crossed true-breeding tall (Parental generation, P) and true-breeding dwarf plants (P).
2. He collected the seeds (F1 generation) and grew them. All F1 plants were tall. The dwarf trait did not appear in the F1.
3. He then self-pollinated the F1 tall plants.
4. In the F2 generation, both tall and dwarf plants appeared. The ratio of tall to dwarf plants was approximately 3:1.

Key observations from monohybrid crosses:

• Only one parental trait was expressed in the F1 generation.
• In the F2 generation, both parental traits reappeared.
• The contrasting traits did not show any blending; offspring were either tall or dwarf, not intermediate.
• The ratio of the expressed traits in the F2 generation was approximately 3:1.

Based on these observations, Mendel proposed that discrete units, which he called 'factors', are passed down unchanged from parents to offspring through gametes. These 'factors' are now known as genes.

• Genes are the units of inheritance and carry information for specific traits.
• Genes exist in slightly different forms called alleles, which code for contrasting traits (e.g., tall and dwarf are alleles for the height gene).
• In diploid organisms, genes occur in pairs (as two alleles).

We use symbols for alleles: a capital letter for the trait expressed in F1 (dominant), and a small letter for the other trait (recessive). For height, T represents the allele for tallness, and t represents the allele for dwarfness.

• A true-breeding tall plant has the allele pair TT (homozygous).
• A true-breeding dwarf plant has the allele pair tt (homozygous).

The genetic makeup (allelic composition) is called the genotype (e.g., TT, Tt, tt). The observable characteristic is called the phenotype (e.g., tall, dwarf).

In the cross between TT and tt, the F1 genotype is Tt. Since the F1 plants were tall, the trait 'Tall' is dominant over 'Dwarf'. The allele T is dominant, and the allele t is recessive.

Alleles can be identical (as in homozygotes TT and tt) or dissimilar (as in heterozygote Tt). A plant with genotype Tt is heterozygous for the height gene and is called a monohybrid. The cross between TT and tt is a monohybrid cross.

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Law Of Dominance

Mendel's observations on monohybrid crosses led him to formulate the Law of Dominance. It states:

1. Characters (traits) are controlled by discrete units called factors (genes).
2. Factors (alleles) occur in pairs in an organism.
3. In a pair of dissimilar factors (alleles), one member of the pair dominates (dominant allele) the other (recessive allele).

This law explains why only one parental trait appears in the F1 of a monohybrid cross and why both traits appear in the F2 in a 3:1 ratio.

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Law Of Segregation

This law is based on the observation that the recessive trait reappears in the F2 generation without any blending. It states:

• The two alleles of a gene pair segregate (separate) from each other during gamete formation, such that each gamete receives only one allele.
• Alleles do not blend.

A homozygous parent (TT or tt) produces gametes with only one type of allele (T or t, respectively). A heterozygous parent (Tt) produces two types of gametes (with allele T or allele t) in approximately equal proportion ($50\%$ T and $50\%$ t).

The formation of gametes and offspring genotypes can be visualised using a Punnett Square, a graphical method developed by Reginald C. Punnett.

In the F1 (Tt x Tt) cross: - Male gametes: $1/2$ T, $1/2$ t - Female gametes: $1/2$ T, $1/2$ t

Possible F2 genotypes from random fertilisation:

• TT ($1/2$ Male T x $1/2$ Female T) = $1/4$ TT
• Tt ($1/2$ Male T x $1/2$ Female t + $1/2$ Male t x $1/2$ Female T) = $1/4$ Tt + $1/4$ Tt = $1/2$ Tt
• tt ($1/2$ Male t x $1/2$ Female t) = $1/4$ tt

F2 Genotypic Ratio: $1/4$ TT : $1/2$ Tt : $1/4$ tt, or 1 : 2 : 1

F2 Phenotypic Ratio: - Tall (TT and Tt): $1/4 + 1/2 = 3/4$ Tall - Dwarf (tt): $1/4$ dwarf - Phenotypic Ratio: $3/4$ Tall : $1/4$ Dwarf, or 3 : 1

Since TT and Tt individuals are phenotypically identical (Tall), the dominant phenotype is seen in a 3:1 ratio in F2.

To determine the genotype of an individual showing the dominant phenotype (e.g., a tall F2 plant, which could be TT or Tt), a test cross is performed. A test cross involves crossing the individual with the dominant phenotype with a homozygous recessive parent (e.g., crossing a tall plant with a dwarf plant tt).

If the offspring of the test cross show both dominant and recessive phenotypes in a 1:1 ratio, the genotype of the tested individual is heterozygous (Tt). If all offspring show the dominant phenotype, the genotype of the tested individual is homozygous dominant (TT).

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Incomplete Dominance

In some cases, the F1 hybrid phenotype does not completely resemble either parent but is an intermediate between the two. This is called incomplete dominance.

Example: Flower color inheritance in the dog flower (Snapdragon, Antirrhinum sp.).

• Cross between true-breeding red-flowered (RR) and white-flowered (rr) plants.
• F1 generation (Rr) has pink flowers (intermediate phenotype).
• Self-pollination of F1 (Rr x Rr) produces F2 generation with a phenotypic ratio of 1 Red (RR) : 2 Pink (Rr) : 1 White (rr).
• The genotypic ratio (1:2:1) is the same as a standard Mendelian cross, but the phenotypic ratio is also 1:2:1, different from the 3:1 dominant:recessive ratio. This is because the heterozygote (Rr) has a distinct phenotype (Pink).

Explanation of Dominance: Dominance is related to how the gene product functions. A gene carries information to produce a specific product, often an enzyme that modifies a substrate (S to S'). The two alleles in a diploid organism might be slightly different.

• The 'normal' allele produces the functional enzyme.
• A modified allele might produce a normal, less efficient, non-functional, or no enzyme.

If the modified allele produces a functional product (normal or less efficient) or its effect is masked by the product of the unmodified allele, the phenotype might be the same as the one produced by the unmodified allele. The unmodified allele is then considered dominant, and the modified allele (which doesn't produce a functional product or its effect is masked) is usually recessive. The recessive phenotype is often due to the absence of the functional enzyme product.

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Co-Dominance

In co-dominance, the F1 generation resembles both parents, meaning both alleles express themselves simultaneously in the heterozygote.

A classic example is the ABO blood grouping in humans, controlled by the gene I. This gene determines the type of sugar polymer on the surface of red blood cells.

• Gene I has three alleles: I^A, I^B, and i.
• Alleles I^A and I^B produce slightly different sugars.
• Allele i does not produce any sugar.

Humans are diploid, so an individual carries any two of these three alleles.

• I^A is dominant over i: Genotype I^Ai results in phenotype A.
• I^B is dominant over i: Genotype I^Bi results in phenotype B.
• I^A and I^B are co-dominant: When both alleles are present (genotype I^AI^B), both express themselves, resulting in phenotype AB (red blood cells have both A and B types of sugars).

There are 6 possible genotypes and 4 possible phenotypes for ABO blood groups:

Allele from Parent 1	Allele from Parent 2	Genotype of offspring	Blood types of offspring (Phenotype)
IA	IA	IAIA	A
IA	IB	IAIB	AB
IA	i	IAi	A
IB	IA	IAIB	AB
IB	IB	IBIB	B
IB	i	IBi	B
i	i	ii	O

The ABO blood grouping also demonstrates multiple alleles, where more than two alleles exist for a single gene within a population (though an individual can only have two). Multiple alleles are studied at the population level.

Pleiotropy vs. Multiple Alleles: Multiple alleles involve different variations of a single gene affecting one trait. Pleiotropy involves a single gene affecting multiple different phenotypes.

Sometimes, a single gene can influence multiple phenotypes. For example, the gene controlling starch synthesis in pea seeds has alleles B (large starch grains, round seed) and b (small starch grains, wrinkled seed).

• Genotype BB: Large starch grains, round phenotype.
• Genotype bb: Small starch grains, wrinkled phenotype.
• Genotype Bb: Intermediate starch grain size, round phenotype (since round is dominant over wrinkled).

If we consider seed shape as the phenotype, B is dominant over b. If we consider starch grain size, the alleles show incomplete dominance (Bb has intermediate size).

This shows that dominance is not an inherent property of an allele but depends on the gene product, the specific trait examined, and how the product influences that trait.

Inheritance Of Two Genes

Mendel extended his studies to crosses involving plants that differed in two characters simultaneously. This is called a dihybrid cross.

Example: Crossing a pea plant with round, yellow seeds (true-breeding) with a pea plant having wrinkled, green seeds (true-breeding).

• Parental Genotypes (P): Round Yellow (RRYY) x Wrinkled Green (rryy).
• Gametes from RRYY: RY
• Gametes from rryy: ry
• F1 generation: All plants had genotype RrYy and phenotype Round, Yellow.

This F1 result confirmed that yellow is dominant over green color, and round shape is dominant over wrinkled shape, just as in separate monohybrid crosses.

Mendel then self-pollinated the F1 (RrYy) plants.

In the F2 generation, he observed four combinations of traits:

• Round, Yellow
• Wrinkled, Yellow
• Round, Green
• Wrinkled, Green

The F2 generation showed a phenotypic ratio of approximately 9 : 3 : 3 : 1.

• 9/16 were Round, Yellow
• 3/16 were Wrinkled, Yellow
• 3/16 were Round, Green
• 1/16 were Wrinkled, Green

When considering each trait separately in the F2, the original 3:1 ratio was maintained:

• Yellow : Green = $(9+3) : (3+1) = 12 : 4 = 3 : 1$
• Round : Wrinkled = $(9+3) : (3+1) = 12 : 4 = 3 : 1$

This indicates that the inheritance of seed color is independent of the inheritance of seed shape.

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Law Of Independent Assortment

Based on his observations from dihybrid crosses, Mendel proposed the Law of Independent Assortment. It states that:

• When two pairs of traits (genes) are combined in a hybrid (heterozygote), the segregation of one pair of characters is independent of the segregation of the other pair of characters.

This means that alleles of different genes assort independently into gametes during meiosis.

For the F1 dihybrid RrYy, the alleles R/r segregate independently of Y/y. - The gametes receive either R or r (50% each). - The gametes receive either Y or y (50% each). - Since segregation is independent, a gamete with R can have either Y or y with equal probability ($50\%$). Similarly, a gamete with r can have Y or y with equal probability ($50\%$).

This results in four possible gamete genotypes from an RrYy individual, each with a frequency of $1/4$ or $25\%$:

• RY (R with Y)
• Ry (R with y)
• rY (r with Y)
• ry (r with y)

The Punnett square for the F1 self-cross (RrYy x RrYy) shows how these gametes combine to produce the F2 generation, illustrating the 9:3:3:1 phenotypic ratio.

To determine the genotypic ratio in the F2 of a dihybrid cross using the Punnett Square (Figure 5.7):

S.No.	Genotype(s) found in F2	Frequency in F2	Phenotype
1	RRYY	1/16	Round, Yellow
2	RRYy	2/16	Round, Yellow
3	RrYY	2/16	Round, Yellow
4	RrYy	4/16	Round, Yellow
Total Round, Yellow		9/16
5	RRyy	1/16	Round, Green
6	Rryy	2/16	Round, Green
Total Round, Green		3/16
7	rrYY	1/16	Wrinkled, Yellow
8	rrYy	2/16	Wrinkled, Yellow
Total Wrinkled, Yellow		3/16
9	rryy	1/16	Wrinkled, Green
Total Wrinkled, Green		1/16

F2 Genotypic Ratio: 1 RRYY : 2 RRYy : 2 RrYY : 4 RrYy : 1 RRyy : 2 Rryy : 1 rrYY : 2 rrYy : 1 rryy -- This simplifies to a complex ratio, not 9:3:3:1. The 9:3:3:1 is the phenotypic ratio.

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Chromosomal Theory Of Inheritance

Mendel's work, published in 1865, remained largely unknown until 1900 for several reasons:

• Limited communication made widespread publicity difficult.
• His concept of discrete, non-blending 'factors' was not accepted by contemporaries who observed continuous variation in nature.
• His use of mathematics in biology was novel and initially met with resistance.
• He could not provide physical proof for his 'factors'.

In 1900, three scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak, independently rediscovered Mendel's laws.

Around the same time, advancements in microscopy allowed scientists to observe cell division clearly. Structures within the nucleus, called chromosomes (due to their ability to be stained), were seen to double and divide during cell division.

By 1902, the behavior of chromosomes during meiosis was well understood. Walter Sutton and Theodore Boveri noticed that the behavior of chromosomes during meiosis was remarkably parallel to the behavior of Mendel's genes ('factors').

Comparison of Chromosome and Gene Behaviour:

A (Chromosomes)	B (Genes)
Occur in pairs (homologous chromosomes).	Occur in pairs (alleles).
Segregate during gamete formation (meiosis) so that only one chromosome from each pair goes to a gamete.	Segregate during gamete formation (meiosis) so that only one allele from each pair goes to a gamete.
One pair of chromosomes segregates independently of another pair (Independent assortment of chromosomes).	One pair of genes/alleles segregates independently of another pair (Law of Independent Assortment).

In the table above, Column A represents chromosomes, and Column B represents genes. This is decided because chromosomes were observed as physical structures during cell division, while genes were initially abstract 'factors' proposed by Mendel.

During Anaphase I of meiosis, homologous chromosome pairs align and separate. The orientation of one pair at the metaphase plate is independent of the orientation of another pair. This independent assortment of chromosomes corresponds to Mendel's Law of Independent Assortment of genes.

Sutton and Boveri synthesised Mendel's principles with the knowledge of chromosome behavior, proposing the Chromosomal Theory of Inheritance. This theory states that genes are located on chromosomes, and the segregation and independent assortment of chromosomes during meiosis account for the patterns of inheritance observed by Mendel.

Experimental verification of the chromosomal theory was provided by Thomas Hunt Morgan and his colleagues using the fruit fly, Drosophila melanogaster.

Drosophila was a suitable experimental organism because:

• They could be easily grown in the laboratory.
• They have a short life cycle (about two weeks).
• A single mating produces many offspring.
• There is clear sexual dimorphism (males and females are easily distinguishable).
• They have several observable hereditary variations.
• They have only 4 pairs of chromosomes, which are easy to study.

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Linkage And Recombination

Morgan conducted dihybrid crosses in Drosophila, similar to Mendel's pea crosses. For example, he crossed yellow-bodied, white-eyed females with brown-bodied, red-eyed males.

He observed that the ratio in the F2 generation significantly deviated from the expected 9:3:3:1 Mendelian ratio when the two genes (for body color and eye color) were on the same chromosome (sex-linked genes on the X chromosome).

He found that the proportion of offspring with parental gene combinations was much higher than the proportion with non-parental (recombinant) combinations.

Morgan concluded that genes located on the same chromosome are physically associated or 'linked'. He coined the term linkage to describe the physical association of genes on a chromosome and recombination to describe the generation of non-parental gene combinations.

Morgan's group found that:

• Some genes on the same chromosome were tightly linked, showing very low recombination frequency (e.g., white and yellow genes showed 1.3% recombination).
• Others were loosely linked, showing higher recombination frequency (e.g., white and miniature wing genes showed 37.2% recombination).

Morgan's student, Alfred Sturtevant, used the frequency of recombination as a measure of the distance between genes on a chromosome. Higher recombination frequency indicates a greater distance between genes. This led to the development of genetic maps, which show the relative positions of genes on chromosomes.

Genetic maps are now important tools, including in projects like the Human Genome Project, to aid in sequencing and understanding genomes.

Polygenic Inheritance

Mendel's studies focused on qualitative traits with distinct categories (like tall or dwarf). However, many traits show a continuous range of variation across a population (e.g., human height, skin color).

Such traits are called polygenic traits. They are typically controlled by three or more genes (polygenes).

Polygenic inheritance also involves the influence of the environment on the phenotype.

In polygenic inheritance, the effect of each allele is additive. The phenotype is a cumulative reflection of the contribution of each dominant allele across all the genes involved.

Example: Human skin color. Assume skin color is controlled by three genes (A, B, C) with dominant alleles (A, B, C) contributing to dark skin and recessive alleles (a, b, c) to light skin.

• Genotype AABBCC: Darkest skin color (maximum dominant alleles).
• Genotype aabbcc: Lightest skin color (all recessive alleles).
• Genotype with three dominant and three recessive alleles (e.g., AaBbCc, AABbcc, etc.): Intermediate skin color.

The intensity of skin color is determined by the number of dominant alleles present in the genotype.

Pleiotropy

While typically one gene affects one trait, in some cases, a single gene can exhibit multiple phenotypic expressions. Such a gene is called a pleiotropic gene.

This often occurs when a gene affects a fundamental metabolic pathway, and disruption of that pathway impacts several different traits.

Example: The disease Phenylketonuria in humans. This autosomal recessive disorder is caused by a mutation in a single gene that codes for the enzyme phenylalanine hydroxylase.

Lack of this enzyme leads to the accumulation of phenylalanine and its derivatives. This single genetic defect results in multiple seemingly unrelated symptoms (pleiotropic effects):

• Mental retardation (due to accumulation of substances in the brain).
• Reduction in hair pigmentation.
• Reduction in skin pigmentation.

Sex Determination

The mechanism by which the sex of an individual is determined has been a subject of genetic study. Cytological observations in insects provided early clues about the chromosomal basis of sex determination.

In 1891, Henking observed a specific nuclear structure during spermatogenesis in some insects. He noted that $50\%$ of sperms received this structure, while the other $50\%$ did not. He called this the 'X body'.

Later research identified the X body as a chromosome, which was named the X-chromosome. Chromosomes involved in sex determination were called sex chromosomes, while the remaining chromosomes were called autosomes.

Two main types of sex determination mechanisms based on sex chromosomes are observed:

• Male Heterogamety: Males produce two different types of gametes regarding sex chromosomes.
  • XO type: Females have a pair of X chromosomes (XX), producing only X-carrying gametes. Males have only one X chromosome (XO, lacking a Y), producing gametes with either X or no sex chromosome (O). Offspring sex depends on whether the sperm carries X or O. Total chromosome number differs between sexes. Example: Grasshopper.
  • XY type: Females have a pair of X chromosomes (XX), producing only X-carrying gametes. Males have one X and one Y chromosome (XY), producing gametes with either X or Y chromosome. Offspring sex depends on whether the sperm carries X or Y. Total chromosome number is the same in both sexes. Example: Humans, Drosophila.
• Female Heterogamety: Females produce two different types of gametes regarding sex chromosomes.
  • ZW type: Males have a pair of Z chromosomes (ZZ), producing only Z-carrying gametes. Females have one Z and one W chromosome (ZW), producing gametes with either Z or W chromosome. Offspring sex depends on whether the ovum carries Z or W. Total chromosome number is the same in both sexes. Example: Birds, some reptiles, some insects.

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Sex Determination In Humans

Humans have the XY type of sex determination.

• Each human cell has 23 pairs of chromosomes (46 chromosomes total).
• 22 pairs are autosomes, identical in males and females.
• 1 pair is sex chromosomes. Females have XX, males have XY.

During gametogenesis:

• Females produce only one type of ovum, carrying an X chromosome ($22 + \text{X}$).
• Males produce two types of sperms in equal proportions: $50\%$ carry an X chromosome ($22 + \text{X}$) and $50\%$ carry a Y chromosome ($22 + \text{Y}$).

Fertilisation:

• If an X-carrying sperm fertilises the ovum (X), the zygote is XX ($44 + \text{XX}$) and develops into a female.
• If a Y-carrying sperm fertilises the ovum (X), the zygote is XY ($44 + \text{XY}$) and develops into a male.

Since the probability of an X-sperm or a Y-sperm fertilising the egg is $50\%$, there is always a $50\%$ chance of having a male or a female child in each pregnancy.

This clearly shows that the sex of the child is determined by the type of sperm provided by the father, not by the mother. Blaming women for having female children is scientifically incorrect.

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Sex Determination In Honey Bee

Sex determination in honey bees follows the haplodiploid system, based on the number of chromosome sets an individual receives.

• An offspring formed from the fusion of a sperm and an egg is diploid ($2n=32$ chromosomes) and develops into a female (queen or worker).
• An unfertilised egg develops into a male (drone) by parthenogenesis. Males are haploid ($n=16$ chromosomes).

Characteristics of the haplodiploid system:

• Males (drones) are haploid.
• Males produce sperms by mitosis (not meiosis).
• Males do not have fathers and thus cannot have sons.
• Males have a grandfather (their mother's father) and can have grandsons (sons of their daughters).

Mutation

Mutation is a phenomenon that causes alterations in the DNA sequences of an organism. These changes can lead to variations in the organism's genotype and consequently its phenotype.

Along with recombination during sexual reproduction, mutation is a source of genetic variation.

Mutations can occur at different levels:

• Chromosomal aberrations: Changes in the structure or number of chromosomes. This can happen due to loss (deletions) or gain (insertions/duplications) of segments of DNA. Chromosomal aberrations are often observed in cancer cells.
• Point mutation: Change in a single base pair in the DNA sequence. A classical example is sickle cell anemia.
• Frame-shift mutations: Insertions or deletions of base pairs (except in multiples of three), which shift the reading frame of the genetic code during protein synthesis, often leading to non-functional proteins.

Mutations can be induced by various factors called mutagens, which can be chemical or physical agents. For example, UV radiation is a physical mutagen.

Genetic Disorders

Genetic disorders are conditions caused by abnormalities in an individual's genes or chromosomes. The study of such disorders in human families is facilitated by tracking the inheritance pattern of traits over several generations.

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Pedigree Analysis

Since controlled breeding experiments are not possible in humans, geneticists use pedigree analysis. This involves studying the inheritance pattern of a particular trait, abnormality, or disease across multiple generations within a family, represented visually as a family tree.

Pedigree analysis is a powerful tool for tracing the mode of inheritance of traits and identifying whether a disorder is inherited, its pattern (dominant/recessive, autosomal/sex-linked), and estimating the probability of its occurrence in future generations.

Standard symbols are used in pedigree charts to represent individuals and relationships.

Genetic information is carried by DNA in chromosomes and transmitted from parents to offspring. Occasionally, changes (mutations) occur in the DNA, which can lead to genetic disorders.

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Mendelian Disorders

These genetic disorders are caused by changes or mutations in a single gene. Their inheritance pattern follows the principles of Mendelian genetics (Law of Dominance, Law of Segregation, etc.).

Mendelian disorders can be dominant or recessive, and can be located on autosomes (autosomal) or sex chromosomes (sex-linked).

Pedigree analysis can help determine if a trait is dominant or recessive and if it is autosomal or sex-linked.

Common Mendelian disorders include Haemophilia, Cystic fibrosis, Sickle-cell anaemia, Colour blindness, Phenylketonuria, Thalassemia, etc.

Colour Blindness: A sex-linked recessive disorder, usually due to a defect in the red or green cones of the eye, causing difficulty distinguishing between red and green colors. The mutated genes are on the X chromosome.

• Occurs more frequently in males ($~8\%$) than females ($~0.4\%$) because males have only one X chromosome.
• A male receives his X chromosome from his mother. If the mother is a carrier (heterozygous for the recessive allele), her son has a $50\%$ chance of being color blind.
• A female is color blind only if she is homozygous recessive, meaning her mother is at least a carrier and her father is color blind (a rare combination).

Haemophilia: A sex-linked recessive bleeding disorder. A defect in a single gene on the X chromosome affects the production of a protein required for blood clotting.

• Affected individuals experience non-stop bleeding from even a minor cut.
• Transmitted from unaffected carrier females to their male offspring.
• A female becoming haemophilic is extremely rare, requiring the mother to be at least a carrier and the father to be haemophilic (which is often lethal before reproductive age).
• The famous pedigree of Queen Victoria showed her as a carrier, transmitting the trait to some descendants in European royal families.

Sickle-cell anaemia: An autosome-linked recessive trait. It is inherited when both parents are carriers (heterozygous).

• Controlled by a single allele pair: Hb^A (normal) and Hb^S (sickle cell).
• Only homozygous individuals for Hb^S (Hb^SHb^S) show the severe diseased phenotype.
• Heterozygous individuals (Hb^AHb^S) are carriers and appear normal but may exhibit the 'sickle-cell trait' under conditions of low oxygen tension. They have a $50\%$ chance of passing the Hb^S allele to offspring.
• The defect is caused by a point mutation in the beta-globin gene. A single base substitution (${\text{GAG}} \to {\text{GUG}}$) at the sixth codon leads to the substitution of Glutamic acid (Glu) by Valine (Val) at the sixth position of the beta-globin chain of haemoglobin.
• Under low oxygen conditions, the mutant haemoglobin polymerises, causing red blood cells to change from a biconcave disc shape to an elongated sickle shape.

Phenylketonuria: An autosomal recessive metabolic disorder. Affected individuals lack the enzyme phenylalanine hydroxylase, necessary to convert the amino acid phenylalanine into tyrosine.

• Phenylalanine accumulates and is converted into phenylpyruvic acid and other harmful derivatives.
• Accumulation in the brain causes mental retardation.
• These substances are also excreted in urine due to poor kidney absorption.

Thalassemia: An autosome-linked recessive blood disease. Transmitted from unaffected carrier parents.

• Caused by mutation or deletion of genes controlling globin chain synthesis, resulting in a reduced rate of synthesis of alpha or beta globin chains of haemoglobin.
• This leads to the formation of abnormal haemoglobin molecules and causes anaemia.
• Classified as alpha-thalassemia (reduced alpha-globin synthesis) or beta-thalassemia (reduced beta-globin synthesis).
• Alpha-thalassemia genes (HBA1, HBA2) are on chromosome 16; beta-thalassemia gene (HBB) is on chromosome 11.
• Distinction from Sickle-cell anaemia: Thalassemia is a quantitative problem (too few globin molecules), while sickle-cell anaemia is a qualitative problem (abnormally functioning globin molecules).

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Chromosomal Disorders

These disorders are caused by the absence, excess, or abnormal arrangement of one or more chromosomes.

Examples of chromosomal abnormalities:

• Aneuploidy: Gain or loss of a chromosome due to failure of chromatids to separate properly during cell division (non-disjunction).
  • Trisomy: Gain of an extra copy of a chromosome (e.g., Trisomy 21 in Down's syndrome).
  • Monosomy: Loss of one chromosome from a pair (e.g., Monosomy X in Turner's syndrome).
• Polyploidy: Increase in the whole set of chromosomes due to failure of cytokinesis after telophase. More common in plants.

Normal human cells have 46 chromosomes (22 pairs of autosomes + 1 pair of sex chromosomes). Changes in this number lead to serious disorders.

Common chromosomal disorders:

• Down’s Syndrome: Caused by the presence of an extra copy of chromosome 21 (Trisomy 21). First described by Langdon Down.
  • Characteristics: Short stature, small round head, furrowed tongue, partially open mouth, broad palm with a characteristic crease, retarded physical, psychomotor, and mental development.
• Klinefelter’s Syndrome: Caused by the presence of an additional X chromosome in males, resulting in a karyotype of 47, XXY.
  • Characteristics: Overall masculine development but also expression of some feminine characteristics (like breast development - gynaecomastia). Affected individuals are sterile.
• Turner’s Syndrome: Caused by the absence of one X chromosome in females, resulting in a karyotype of 45, X0.
  • Characteristics: Affected females are sterile due to rudimentary ovaries. Other features include lack of secondary sexual characters and short stature.

Chromosomal disorders can be identified by analysing the karyotype (a complete set of chromosomes arranged in pairs).

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