L24: The human genome and disease

• genetic variations or mutations are a driving force for evolution
• mutations can have a beneficial effect, no effect or a deleterious (harmful) effect on the organism
• the vast majority of mutations have no effect
• the outcome of a mutation can depend on environmental effects or other genes
• mutations can be inherited or acquired and are permanent changes to the DNA sequence
• mutations that are inherited are called germline mutations and are passed on via gametes
• mutations can also be acquired by somatic cells if the DNA gets damaged or is copied incorrectly. somatic mutations are not passed on to the next generation.
• mutations in a single gene have different effects
• mutations are messy and inconsistent
• humans are diploid, meaning that have two copies of each of there genes, 1 parental, 1 maternal
• a mutation allele can thus be either heterozygous (1 mutant, 1 wild type) or homozygous (both alleles mutant)
• a dominant mutation is one that causes a phenotype when heterzygous
• a recessive mutation is one that causes a phenotype only when homozygous
• for mutation to have a phenotype, it must affect the function of a gene. a mutation might break a gene to cause it not to work as well as normal or not work at all
• breaking a gene is called 'loss of function' mutation. they are often recessive because a normal copy of the gene exists on the other chromosomes, which can replace the lost function
• sometimes a mutation can cause a gene to work too well, or to do something unexpected. this is called 'gain of function'.
• gain of function mutations are often dominant because having an allele tat works too well or does something, will not be replaced by the normal copy of the gene
• by examining the inheritance pattern of an allele, we can determine if it is dominant and recessive. also if it is X-linked, Y-linked or autosomal
• autosomal recessive are not seen in every generation of an affected family. it is passed on by 2 asymptomatic carriers. male and females are equally likely to inherit it.
• autosomal dominant occurs commonly in a pedigree. affected individuals have an affected parent. males and females re equally likely to inherit it.
• X-linked recessive, fathers cannot passed these to their sons. there is no male-to-male transmission and most often affects males.
• we determine the inheritance patten is to examine the pedigree and look for individuals that break the above rules. then we identify carriers who do not have the condition, if there are non, this might mean the condition is dominant.
• finding potential disease genes

  A) sequence genome

  B) map to human reference

  C) common variants

  D) novel variants

  E) benign

  F) harmful

  G) validate and test

  
• most disorders appear to have a genetic basis but do not follow straightforward inheritance patterns
• polygenic disorders involve several genes acting together or environmental factors interacting with genes. examples include: obesity, diabetes, gout, bipolar disorder. identifying them is hard
• finding disorder

  A) cases

  B) controls

  C) identify variation

  D) cases

  E) controls

  F) common variants

  
• such diseases come about through combination of variants and the environment. different sufferers may have different disease mechanisms
• most genetic disorders are probabilistic, not deterministic