Genetics

• Iceland is well-suited for genomics research for a few reasons
• Iceland's population


  • Relative isolation has resulted in a population of approximately 320,000 that is almost entirely descended from a single family tree
  • Data about the population's genealogy has been extensively recorded since 740 AD, and sits in an accessible database called Íslendingabók or book of Icelanders
• Founder effect


  In population genomics, the lack of diversity limits the number of genomic variants (differences between people), and allows usually rare variants to become common enough in the population to be more easily noticed and studied
• Íslendingabók was recently connected to an application that quickly identifies the degree of relatedness between any two people
• Electronic medical records, part of the country's national healthcare system, easily link genotype (the sequence of bases that make up a person's DNA) to phenotype (the observable characteristics of a person)
• Researchers' approach


  1. Fully sequenced 2,636 Icelanders

  2. Compared the genomes to find 20 million SNPs and 1.5 million insertions and deletions

  3. Examined 104,220 Icelanders and projected their whole genomes based on similarities to the fully sequenced group

  4. Annotated the variants to identify genes and protein-coding regions

  5. Focused on rare variants more likely to be linked to disease
• Loss-of-function (LOF) variants


  Variants that completely disrupt the function of a gene
• Each individual was found to have, on average, 149 LOF genomic variants, with only 1.4 of these being rare in the population
• Researchers found a large number of homozygotes in the Icelandic population, especially in offspring of parents from the same region
• 7.7% of the study population, or 8,041 individuals, were found to be complete knockouts for a total of 1,171 genes, 790 of which occurred less than five times in the study population
• The more rare the LOF mutation, the more likely it is to cause disease
• Some disease-linked alleles occurred at a higher frequency in the Icelandic population, but were not frequently found in more diverse populations
• Researchers found a strong association between LOF variants in the gene ABCA7 and Alzheimer's disease, and an association between the gene MYL4 and atrial fibrillation
• The United States will soon launch a large population-based study at least 1 million people as part of President Obama's Precision Medicine Initiative
• Researchers in the US will face challenges in collecting medical data due to the country's fragmented health care system
• By understanding our population and the role of genomics in health, scientists and clinicians are on the path to improving disease diagnostics and treatment
• Inheritance (Genotype/Phenotype)


  The process by which genetic information is passed from parents to offspring

  
• Inheritance


  1. At fertilization, chromosomes from each parent are inherited by the offspring

  2. The zygote has the full complement of DNA (i.e., 46 chromosomes), inheriting one of each of the homologous chromosomes from each of the parents

  
• Homologous chromosomes


  • Chromosomes that have genes of specific traits in the same order (i.e., same gene loci)
  • 23 pairs of homologous chromosomes
• Allele


  A variant form of a gene
• Alleles coding for the same gene


  Separate during gamete formation
• Cell undergoing mitosis (before S phase)


  Homologous chromosomes
• Cell undergoing mitosis (after S phase)


  Sister chromatids
• Gene expression (central dogma)


  The flow of information from DNA to RNA to protein
• Genotype


  Dictates phenotype
• Characteristics of organisms


  • Governed by units of inheritance called genes
  • Each trait is controlled by two forms of a gene called alleles
  • When alleles are nonidentical, the dominant allele masks the recessive allele

  
• Fibrillin is essential for the formation of elastic fibers