HBG 25 ( Multifactorial Polygenic)

• Non-disjunction is the failure of chromosome pairs to separate properly during cell division
• Non-disjunction can result in an imbalance of chromosomes, known as aneuploidy
• Alterations of chromosome number can lead to numerical chromosomal disorders
• Examples of numerical chromosomal disorders include Down syndrome (trisomy 21), Patau syndrome (trisomy 13), and Edward syndrome (trisomy 18)
• Down syndrome (trisomy 21) is associated with a flat facial profile, congenital heart malformations, and delayed puberty
• Patau syndrome (trisomy 13) can present with cleft lip and palate, congenital heart disease, and severe mental retardation
• Edward syndrome (trisomy 18) is more common in females and can lead to excess spontaneous abortions in affected males
• Non-disjunction of sex chromosomes can result in conditions like Klinefelter syndrome (47, XXY males) and Turner's syndrome (Monosomy X)
• Klinefelter syndrome is characterized by tall stature, small testes, and an increased risk of breast cancer
• Turner's syndrome presents with short stature, ovarian failure, and congenital heart defects
• Deletions and duplications of chromosome segments can lead to disorders like Cri du chat syndrome and Prader-Willi syndrome
• Fragile X syndrome is the most common cause of severe mental retardation after Down syndrome and is characterized by a fragile X chromosome tip and repetitive speech
• Polygenic Traits and Disorders
• Polygenic traits result from the combined action of alleles of more than one gene
• Polygenic multifactorial disorders involve both genetic and non-genetic factors in their development
• Multifactorial polygenic inheritance involves the interaction of multiple genes and environmental factors in trait expression
• Models of Multifactorial Polygenic traits include the Continuous/Additive Model and the Discontinuous/Threshold Model
• Quantitative inheritance follows a normal distribution, while qualitative traits are either present or absent based on a threshold of liability being crossed
• Multifactorial polygenic disorders involve many genes at different loci, with each gene exerting a small additive effect
• No gene is dominant or recessive to another in polygenic disorders
• Liability for multifactorial disorders depends on predisposing genes and exposure to environmental factors
• Heritability is the proportion of total phenotypic variance caused by additive genetic variance in a certain population at a certain time
• Family studies, twin studies, and adoption studies are used to estimate genetic contributions to diseases
• Relative risk studies in families can show the influence of genetic variation on disease occurrence
• Twin studies compare monozygotic (MZ) and dizygotic (DZ) twins to study genetic and environmental influences on traits
• Hypertension is a multifactorial polygenic disorder influenced by genes related to weight, cholesterol, kidney function, and environmental factors
• Alzheimer's disease is influenced by mutations in genes like presenilin and apolipoprotein E, with a higher risk if a first-degree relative is affected
• Schizophrenia is a severe emotional disorder with genetic influences identified through linkage and association studies
• Neural tube defects are caused by abnormal closure of the embryonic neural tube and involve over 80 genes
• Type II Diabetes Mellitus is a multifactorial disorder influenced by genes like glucokinase and environmental factors like high blood pressure and obesity
• Discontinuous Traits

  • Height
  • Skin colour
  • Body mass
  • Fingerprint
  • Hair colour
  • Obesity
  • Hypertension
  • Diabetes
  • Cleft lip & palate
  • Anencephaly
  • Congenital Heart disease
  • Pyloric stenosis
  • Manic-depressive psychosis
  • Schizophrenia
  • Rheumatoid arthritis
  • Gout
• Phenotype

  A continuous range of measurement with only a few distinct phenotypes
• Outcomes for polygenic inheritance

  • Scenario I: 1 Tall (AA), 2 Average (AB/BA), 1 Short (BB)
  • Scenario II: 1 Very Tall (AAAA), 4 Tall (AAAB), 6 Average (AABB), 4 Short (ABBB), 1 Very Short (BBBB)
  • Scenario III: 1 Extreme Tall, 6 Very Tall, 15 Tall, 20 Average, 15 Short, 6 Very Short, 1 Extreme Short
• Genes for 'Tall-ness'

  Inheritance of a polygenic trait involves many genes at different loci, each exerting a small additive/cumulative effect, with no gene being dominant or recessive, leading to quantitative inheritance
• Familial correlation (quantitative) is based on 3 genes & 2 alleles each
• Liability

  All factors that influence the development of a multifactorial disorder, can be genetic or environmental factors, cannot be measured but can be determined from the incidence of the disease in a group using statistics of the normal distribution, units of measurement are SD used to estimate correlation between relatives
• Heritability

  Proportion of the total phenotypic variance of a condition caused by additive genetic variance in a certain population at a certain time, greater value indicates a greater role of genetic factors, H value = 1 means variability is completely due to gene action, H value = 0.2 means 20% of phenotypic variation is due to genetic variation
• Correlation


  A statistical measure of the degree of association of variable phenomena, degree of resemblance or relationship between two parameters
• Gene Hunting

  1. Linkage Analysis

  2. Sibling-Pair Analysis
• Mapping of single-gene disorders is done by studying the co-segregation of genetic markers with disease, pairs of phenotypically similar siblings tend toward excess sharing of relevant chromosomal regions, dissimilar pairs tend toward lower sharing