Genomes and Genomics

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Genomes and Genomics
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Learning Objectives

• By the end of this class you should understand
• The information that may result from sequencing a
  genome
• The techniques and purpose of genetic maps
• The history of sequencing the human genome and
  its future potential
• The primary study and tools of the field of
  bioinformatics
• The relationship between the genome and the
  proteome and exome
• Concerns about ownership and genomes

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Advancing Genetic Knowledge

• Mutations have always been a major foundation for
  understanding genetics
• Without mutations we would all be identical!
• Before genetic sequencing, before even DNA,
  mutations were used to track relationship between
  genes

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Chromosomal Linkage

• A chromosome with two defects will create
  both-or-neither inheritance
• Recall this is chromosomal linkage
• All genes on X chromosome are linked
• Hemophilia and colorblindness showed linkage
• Autosomal linkage took much longer to find

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Chromosomal Linkage

• Nail-Patella Syndrome and Blood Type were finally
  linked
• We now know they are both on chromosome 9
• However, linkage was not total
• Remember crossing over? AKA Chromosomal
  recombination

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Crossing Over

• Recall during meiosis (Prophase I) chromosomes
  will exchange DNA
• This enables us to track what genes are on what
  chromosome
• And where!

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Chromosomal Linkage
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Chromosomal Distance

• The closer two genes are on a chromosome, the
  more frequently they will cross over together
• The farther away they are, the more one will
  recombine without the other
• Percentage of recombination measured in units of
  centimorgans
• 2/16 12.5 12.5 centimorgans distance

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Genetic Cloning

• Thanks to PCR and improved DNA sequencing, many
  genes were mapped to chromosomes starting in the
  1980s
• Huntington's, Cystic Fibrosis, Retinoblastoma,
  etc
• The Human Genome Project was initiated in 1990

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Human Genome Project

• Goal Seq uence entirety of human genome
• Additional goal figure out what genes do what
• Additional goal sequence other animals/plants
• Work got faster and faster as time went on
• Computers were created that could accelerate the
  project

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DNA Sequencing

• Human genome is 3.2 billion DNA bases
• Not the largest, not even close!
• Marbled lungfish genome 132.8 billion DNA bases
• That is NOT a typo!
• Sequencing entire genome took a long time!

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History of Human Genome Project
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Sequencing Methods

• Map-based sequencing locates sequences of DNA
  relative to markers found on each chromosome
• A comprehensive map of which genes are on which
  chromosome can be constructed and measured in
  centimorgans
• Whole genome sequencing slices the entire genome
  into cloned libraries then sequences them all
  using computer technology

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Sequencing Methods
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Genome Sequencing

• Entirety of genome can now be sequenced in days
  instead of years
• Still expensive but getting cheaper!
• The human genome is 98 noncoding
• The coding portion of the human genome is called
  the exome

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Genome vs. Exome

• Exome is the coding portions of DNA only
• Codes for proteins
• A scan of all exons in genome
• 50 times less data to analyze
• Used to screen and diagnose for genetic disorders
• May not catch CNV disorders

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Now What?

• Once you have a genome, what do you do with it?
• The field of bioinformatics addresses what to do
  with this massive amount of data
• Bioinformaticians must be skilled in computer
  science and math (linear algebra and probability)

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Bioinformatics Specialties

• Comparative Genomics
• Studying relationship between different
  animals/plants/bacteria
• Structural Genomics
• Studying structure of proteins produced by genes
• Pharmacogenomics
• How to make drugs to repair diseases

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Bioinformatics Basics

• The most important skill in bioinformatics
  locating a gene!
• Find the gene in the following sequence
• ACAGGAGAAATATACCAATACCGCTTGCGAGAGATCATGGAATCTCGAGC
  GTTATGTGAATGCTGAAAAAAAAAAA
• A bioinformatician can find it!
• Technically the entire sequence is a gene but the
  bioinformatician can find the start codon and the
  upstream promoter region
• Technically the bioinformatician can write a
  computer program to do that for him/her

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Gene Location

• By homing in on clues like the TATA box and CCAAT
  initiator sequence, bioinformaticians can locate
  genes
• This is known as annotation
• Must be compared to protein sequences to have
  introns identified

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Annotation
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Introns and Exons

• The codons (beginning with ATG) form an open
  reading frame (ORF)
• The origin of the term frameshift
• Insertion/deletion mutations may alter the
  frameshift unless they occur in an intron
• Intron variability is much higher than exons!
• Computers can detect all these predictable
  patterns

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Genes in Genome
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Full Genome

• Remember that standard genes comprise only 2 of
  the genome, tops
• Long stretches of DNA are repeated sequences that
  still serve important functions!
• Alterations to these repeated stretches in one
  spot are called single nucleotide polymorphisms

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Junk DNA Alterations

• Single base changes (SNPs) can be compiled into a
  haplotype
• Similar to a bar code of the chromosome
• Reveals where the chromosome was inherited from
  and who else have a closely related chromosome
• Changes to the number of repeated bases are
  called copy number variants

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Copy Number Variants

• CNVs alter the length of a chromosome
• Since DNA can affect expression of genes
  thousands of bases away, CNVs are linked to
  various disorders
• Probably due to variable or reduced expression of
  the associated gene/protein

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Genome vs. Proteome

• Even though there are only 25,000 genes, there
  are over 200,000 proteins
• Possibly up to a million!!
• Due to differential intron/exon splicing
• All the proteins in the body together make the
  proteome
• Studying proteins is called proteomics

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Concerns of Genomics

• Major concern who owns your genome?
• Remember, now genes CANNOT be patented
• Research still belongs to company even if it's
  done with your tissue
• Major concern should we be testing genomes of
  healthy people?
• Especially while information is incomplete!

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Happy Wednesday!