Chromosome Mutations

Chromosome Mutations

12.1 Introduction

• Chromosome mutations are changes in chromosomes.
• Two types of chromosome mutations:
  • Changes in chromosome structure.
  • Changes in chromosome numbers.
• Structural mutations: deletion (deficiency), duplication, translocation, or inversion.
• Mutations in chromosome number: euploidy and aneuploidy.
• Chromosomal mutations can lead to phenotypic abnormalities and human genetic diseases.

12.2 Objectives

• Explain mutations in chromosomal structure.
• Explain mutations in chromosomal number.
• Discuss human diseases caused by chromosomal mutations.
• Describe methods for detecting human genetic diseases.
• Describe methods of pedigree analysis of human genetic diseases.

12.3 Mutations in Chromosome Structure

• Structural mutations include deletion, duplication, translocation, or inversion.
• These changes can lead to loop formation during meiosis.
• Chromosome sets can undergo spontaneous rearrangements.

12.3.1 Deletion (Deficiency)

• Deletion represents a loss of chromosomal material, potentially including one or more genes.
• Example: Chromosome abcdefg losing segment fg.
• Deletion heterozygotes can result in pseudo-dominance, where a recessive allele on the intact chromosome expresses itself as if it were dominant due to the deletion of the corresponding allele on the other chromosome.
• Cri-du-Chat syndrome: caused by a deletion of a large part of the short arm of chromosome 5.
  • Symptoms: cat-like cry, mental retardation, moon face, low birth weight, saddle nose, small mandible, malformed low-set ears.
• Partial deletions of chromosomes 4, 13, and 18 are associated with specific syndromes.

12.3.2 Duplication (Addition)

• Duplication is the presence of a chromosome section in excess of the normal amount.
• The repeated section can be on one pair of homologous chromosomes or transposed to a nonhomologue.
• Duplications are generally less deleterious than deletions and can act as new sources of genetic variation.
• Example: Duplication of segment ab in chromosome abcdefg.

12.3.3 Translocation

• Translocation moves a chromosome segment to another position in the genome.
• Chromosomes can undergo spontaneous rupture or be induced to rupture by ionizing radiation.
• Broken ends can rejoin in a non-homologous position, creating new gene linkages.
• Translocation heterozygotes may have reduced fertility.
• Translocations are an important cause of ill health in human populations.

12.3.3.1 Simple Translocation

• Involves a single break in the chromosome and the transfer of a broken piece directly onto the end of another chromosome.
• Example: Simple translocation of bd from abcdefg to one end of vwxy.

12.3.3.2 Shift (Intercalary) Translocation

• Involves three breaks, where a middle piece from one chromosome is inserted within a break in a nonhomologous chromosome.
• Example: Shift translocation of bc in between x and y involving nonhomologues.

12.3.3.3 Reciprocal Translocation (Interchanges)

• Occur when single breaks in two nonhomologous chromosomes produce an exchange of chromosome segments.
• Example: Reciprocal translocation of segments bc and wx between two homologues.
• Philadelphia chromosome: reciprocal translocation between chromosomes 9 and 22.
  • Found in about 90% of patients with chronic myelocytic leukaemia (CML).
  • t(9;22)(q34;q11) - Philadelphia chromosome, Chronic myeloid leukaemia (CML), ALL
• Reciprocal translocation between chromosomes 8 and 14 causes most cases of Burkitt’s lymphoma, a cancer of the B lymphocytes.
  • t(8;14) - Burkitt's lymphoma (c-myc).

12.3.4 Inversion

• Inversion involves a break in a chromosome segment and the rejoining of the segment after a 180° turn.
• Example: Inversion of the segment cd.
• Pericentric inversions span the centromere, while paracentric inversions do not.
• Inversions can disrupt a gene if they occur in the middle of a gene.
• Paracentric inversions are generally less deleterious than pericentric inversions.

12.4 Mutations in Chromosome Numbers

• Each species has a characteristic number of chromosomes.
• Humans and higher organisms are diploid (2n), with two sets of homologous chromosomes.
• Mutations in the number of sets of chromosomes (ploidy) are common in nature.
• About one-third of flowering plants (angiosperms) have more than two sets of chromosomes.
• Two types of variation in chromosome number:
  • Euploidy.
  • Aneuploidy.

12.4.1 Aneuploidy

• Aneuploidy is the change in the number of individual chromosomes.
• Chromosomes may be added to or subtracted from normal sets.
• One or more whole chromosomes may be absent from or added to the chromosome set.
• Cause: non-disjunction.
• Non-disjunction: both chromosomes (or chromatids) pass to the same pole of a cell instead of opposite poles at anaphase during meiosis.
• Aneuploid conditions are well studied in humans.
• Examples: Down syndrome (Trisomy 21), Klinefelter syndrome (XXY), and Turner syndrome (XO).
• The spontaneous level of aneuploidy in humans is quite high and produces a major proportion of genetic diseases in human populations.

12.4.1.1 Non-disjunction of Sex Chromosomes

• Failure of sex chromosomes in either sex to separate during meiosis results in the production of both normal and rare aneuploid gametes.
• Examples given for non-disjunction in males and females with resulting gametes.
• Fertilization of rare gametes results in various sex chromosomal anomalies and associated abnormal phenotypes in the offspring.

Trisomics (2n + 1) - polysomy

• Examples of viable trisomics in humans:
  • Klinefelter syndrome (XXY): sterile males with effeminate tendencies.
  • XYY syndrome: sterile males that are physically normal but socially deviant.
• Down syndrome: autosomal trisomic caused by non-disjunction of chromosome 21.
  • Maternal-age effect: older mothers have a greater risk of having Down syndrome children.
  • Facial features: eyelids that slant upwards, flat and rounded face.
  • Other symptoms: mental retardation, short stature, relatively small skull, heart defects (in about one-quarter of Down’s children), increased risk of respiratory and ear infections, high risk of leukaemia, coarse, straight hair.

12.4.2 Euploidy

• Euploidy: variation in the number of whole sets (complements) of chromosomes.
• Diploids with two sets of chromosomes are considered normal in eukaryotes.

12.4.2.1 Polyploids

• Organisms with three or more complement sets of chromosomes.
• Examples: triploids (2n=3x), tetraploids (2n=4x), pentaploids (2n=5x), and hexaploids (2n=6x).
• Polyploids are common in plants.
  • Examples: bread wheat, Triticum aestivum (2n=6x=42); potato, Solanum tuberosum (2n = 4x = 48).
• Polyploids are rare in animals; they often fail to develop and are aborted.
• Polyploids can arise due to non-disjunction:
  • Two gametes with unreduced chromosomes fuse to form a tetraploid zygote.
  • A gamete with unreduced chromosomes fuses with a normal gamete to form a triploid zygote.
• Unreduced gametes are formed when there is a failure to form spindles at anaphase during meiosis, resulting in diploid gametes.

12.4.2.2 Monoploids

• Have only one set of chromosomes that develops from unfertilized eggs; very rare.
• Male bees, wasps, and ants are monoploids, developing parthenogenetically from unfertilized eggs.

12.5 Human Genetic Diseases

• Human genetic diseases are inherited from parents.

12.5.1 Detection of Human Genetic Diseases

• The first step toward pedigree analysis of human diseases is the detection of the diseases themselves.
• Prenatal diagnostic methods are used to detect disorders in unborn children.
• Techniques include amniocentesis, chorionic villi sampling, and ultrasound.

12.5.1.1 Amniocentesis

• A sample of amniotic fluid is taken using a syringe and a hypodermic needle around the sixteenth week of pregnancy.
• It is separated into fluid and cells.
• The fluid is used to detect:
  • Neural tube disorders.
  • Biochemical (metabolic) diseases.
• The cells are cultured and used to study:
  • Foetal sex.
  • Chromosomal disorders.
  • Metabolic diseases.

12.5.1.2 Chorionic Villi Sampling

• A sample of finger-like projections called chorionic villi is taken from the chorion.
• The sample is taken using either a transabdominal needle guided by an ultrasound probe or through a transcervical catheter, also guided by an ultrasound probe.
• This technique is used to study foetal sex, metabolic disorders, and chromosomal disorders.
• Produces faster results compared to amniocentesis but cannot detect neural tube defects.

12.5.1.3 Ultra Sound

• Ultrasound is used together with amniocentesis and chorionic villi sampling in locating the placenta, establishing an accurate gestational stage, and excluding multiple pregnancy and foetal death.

12.5.2 Pedigree Analysis of Human Genetic Diseases

• A human pedigree is a chart of an individual's ancestors used in human genetics to analyze Mendelian inheritance of certain traits, especially inherited diseases.
• Pedigree analysis involves collecting information about a particular family and their ancestors to construct a pedigree chart (family tree).
• This chart contains names of people and information about their phenotypes.
• Using this chart, it is possible to predict the risks of a particular couple having a child who might suffer from a particular genetic disorder.
• Consanguinity is the marriage of related individuals (e.g., cousins).
• The propositus is the individual who first draws the geneticist’s attention to a particular family.

12.5.2.1 Autosomal Dominant Traits

• Autosomal traits are carried on the autosomal chromosomes (not on the sex chromosomes).
• Inheritance of autosomal traits is best-studied using dominant traits.
• Clues indicating a trait is not sex-linked (X-linked):
  • Equal numbers of male and female offspring are affected.
  • If the affected male passes the trait to his sons, the gene cannot be on the X-chromosome.
  • If the affected male has affected daughters as well as unaffected daughters, the gene cannot be X-linked dominant.

12.5.2.2 Autosomal Recessive Inheritance

• Autosomal recessive traits are characterized by:
  • Rarity of the trait.
  • Skipping of generations.
  • Consanguineous marriages.

12.5.2.3 Sex-linked Traits

• Sex-linked traits are carried by sex chromosomes (X or Y).
• Sex-linked (X-linked) traits are characterized by:
  • Many more males than females being affected.
  • If caused by a very rare recessive gene, almost all observed cases would be males.
  • Usually, none of the offspring of an affected male will be affected (if his wife is unaffected), but all his daughters will carry the allele, so half their sons, on average, should be affected.

12.5.3 Common Human Genetic Diseases

• Some common human genetic diseases are listed in Table 12.2, including their type of inheritance and allele type.
  • Cystic fibrosis: Autosomal Recessive.
  • PKU: Autosomal Recessive.
  • Sickle cell anaemia: Autosomal Recessive.
  • Colour blindness: X-linked Recessive.
  • Haemophilia: X-linked Recessive.
  • Huntington’s disease: Autosomal Dominant.
  • Muscular dystrophy: X-linked Recessive.

12.6 Revision Exercise

• (Questions listed for review, but answers not provided in the transcript)

12.7 Summary

• Chromosome mutation may be in number (due to missing or extra chromosomal DNA) or in structure (due to an irregular portion of chromosomal DNA).
• Structural mutation may be due to deletion (deficiency), duplication, translocation, or inversion.
• The major two types of mutation in chromosome number are euploidy (changes in the number of whole chromosome sets) and aneuploidy (changes in the number of individual chromosomes).
• Chromosomal mutations are responsible for a number of human genetic diseases such as Down Syndrome, Klinefelter Syndrome, cancers, and sexual abnormalities.
• Methods such as amniocentesis, chorionic villi sampling, and ultrasound have been developed to detect genetic disorders in unborn children.
• Pedigree analysis helps estimate the probability of a couple having a child with a genetic disorder.