Human Genetic Disease

1
Human Genetic Disease

• Chromosomal mutations
• review of meiosis
• non-disjunction
• translocations
• balanced
• unbalanced
• Mitochondrial mutations
• mitochondrial DNA
• mitochondria and disease

2
Meiosis

• process in which chromosomes are divided to
  produce gametes that have only one copy of each
  chromosome
• start out with replicated chromosomes (4
  chromatids)
• independent assortment of alleles
• abnormal meiosis can results in chromosome
  imbalance

3
Meiotic Non-disjunction

• failure of chromosomes to separate in meiosis
  (usually just affects one chromosome)
• aneuploidy (chromosome number differs from normal
  by part of a chromosome set)
• Resulting gamete will either be missing one
  chromosome or have two copies of a chromosome

4
Meiotic non-disjunction

• trisomy
• one extra chromosome
• usually embryonic or fetal lethal
• Trisomy 21 (Down syndrome) 47,XX or XY, 21
• 1/800 births, dependent on maternal age
• some degree of mental retardation, characteristic
  features, slowed growth
• Trisomy 18 (Edwards syndrome) 47,XX or XY, 18
• 1/8000 births, 5 of zygotes develop to term
• severe abnormalities- mental retardation, heart
  malformation
• Klinefelter syndrome 47, XXY 1/1000 males
• tall, long arms, large hands and feet, infertile

5
Meiotic non-disjunction

• monosomy
• missing one chromosome
• autosomes- embryonic lethal
• sex chromosomes
• Turner syndrome 45, X 1/5-10,000 females
• short, infertile, minor distinctive physical
  features, normal intelligence
• nullisomy
• missing a pair of homologues
• preimplantation lethal

6
Changes in chromosome number
fertilization of egg by 2 sperm or diploid egg or
sperm ? lethal
2n
n
failure of first mitotic division ? incompatible
with development
7
Chromosomal rearrangement

• translocations
• breakage of a chromosome and reattachment of that
  part to another chromosome

8
Chromosomal rearrangement

• balanced translocation- a reciprocal exchange

9
Chromosomal rearrangement

• unbalanced translocations
• non-reciprocal exchange
• leads to chromosome imbalance
• partial trisomy or monsomy
• Inherited form of Down Syndrome
• trisomy of portion of 21
• Cri-du-chat syndrome
• partial monsomy of 5 due to deletion

10
Mitochondrial inheritance

• mitochondria possess a small circular genome
  encoding 37 genes
• mitochondria provide 90 of cellular energy
  through oxidative phosphorylation
• process carried out by proteins encoded
  mitochondrially and nuclearly
• recent findings show that mutations in some
  mitochondrial genes cause multi system disorders
  generally affecting CNS, sight, hearing, heart
  and skeletal muscles, kidney and pancreas defects

11
Mitochondrial inheritance

• mitochondria are inherited maternally
• each cell possesses 10,000 mtDNA molecules
• variability and mutation can lead to some cells
  having a mixture of genotypes
• eggs only have about 200 mitochondria - can lead
  to a bottleneck that reduces diversity and leads
  to disorders
• differences in phenotypes between individuals due
  to differences in proportion and tissue
  distribution of mutations
• symptoms include diabetes, dementia, loss of
  sight and hearing
• somatic mutations in mtDNA over time may result
  in age-related disorders and deterioration of
  body function