Genetics: Chromosomal Abnormalities and Genes Mutations Jill Rafael-Fortney, Ph.D. Associate Professor of Molecular & Cellular Biochemistry The Ohio State Wexner Medical Center

Objectives 1.Demonstrate a basic understanding of cytogenetic nomenclature. 2.Describe the types and extent of variation seen in the human genome, including both sequence and structural variation in coding and non-coding sequences. 3.Describe the roles of mutation and polymorphism in both normal human variation and disease. 4.Describe the types of mutations that lead to human disease and their functional consequences.

Types of Genetic Mutations: Aneuploidy  abnormal chromosome number, which is not an exact multiple of the haploid number (n = 23)  Results from abnormal chromosome segregation during mitosis or meiosis  Most cases originate during female meiosis I and risk increases with advancing maternal age

Aneuploidy  Trisomies  Most are embryonic or fetal lethal  Trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) may survive to term  Trisomy 21 (Down syndrome) may survive to age 40 or longer  Written as 47XX+ 21 in the example of a Down’s syndrome female  47XXX or 47XXY, or 47XYY have relatively minor problems and a normal lifespan  Monosomies  Autosomal monosomies are embryonic lethal  45X Turner syndrome – 99% abort spontaneously, survivors are of normal intelligence but infertile and show minor physical signs

Polyploidy  Any multiple of the haploid number of chromosomes (n = 23)  Triploidy most common (3n)  69XXX; 69XXY; 69XYY  Occurs in 1% of all conceptions Livebirths rare  Cause Fertilization by 2 sperm Error in maternal meiosis II

Types of Genetic Mutations: Chromosomal rearrangements  Result from chromosome breakage or recombination between mispaired chromosomes during meiosis.  Deletions : loss of a part of a chromosome Contiguous gene syndromes  Translocations: part of a chromosome is transferred to another chromosome Only cause disease when the break in within an important gene or change the copy number of the gene About 1/1000 infants is born with a symptomatic chromosomal rearrangement. Non-symptomatic rearrangements often account for infertility/miscarriages

Possible stable results of two breaks on a single chromosome Strachan & Read, human Molecular Genetics 2, NCBI Bookshelf

Translocations  Balanced reciprocal translocation  Robertsonian translocation  fusion of q arms of 2 acrocentric chromosomes  Considered balanced since lost p arms contain only repetitive arrays of rRNA genes 3 der(3) der(11) der(14;21) Karyotype nomenclature: 46XX or XYt(3;11) Karyotype nomenclature: 46XX or XYder(14;21)

Types of Genetic Mutations: Single gene mutations  Point mutations – change in a single base pair; 60% of disease causing mutations  Transition – purine replaced by another purine  Transversion – purine to pyrimidine or pyrmidine to purine change  Missense mutation – generates an amino acid change  Nonsense mutation – generates a premature stop codon  Synonymous or silent base change – no resulting amino acid change  Splice site mutation – changes an intron-exon junction or intron branch site  Deletions  Insertions  Mutations in regulatory regions - <1% of disease causing mutations  Mitochondrial mutations – maternal inheritance pattern can cause frameshifts; 20-25% of disease causing mutations

Point mutation examples  Missense mutation  UUA (Leu) → UCA (Ser)  Nonsense mutation  UUA (Leu) → UAA (Stop)  Synonymous or silent base change  UUA (Leu) → UUG (Leu)

Types of Genetic Mutations: Multifactorial disorders  Also called: polygenic diseases or complex diseases  Caused by interacting genetic and environmental risk factors; not a single major mutation  Encompasses most common diseases  Diabetes  Cardiovascular diseases  Allergies  Susceptibility to infection diseases

Alternative or Supplemental Reading  “Principles of Medical Biochemistry” by Gerhard Meisenberg and William H. Simmons; Elsevier, Philadelphia, PA; Pp

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